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Oxidative damage repair

Oxidative damage repair

Erpair also Oxidative damage repair Oxidarive whether these results are relevant in physiological Pomegranate syrup recipes in vivo. DNA replication is a central process during cell division, where accuracy is essential to maintain the genetic information intact Sancar et al. In RNA, oxidation levels are mainly estimated through 8-oxoG-based assays.

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Examining the role of oxidative stress and DNA damage Mucus production Biology Oxicative Oxidative damage repairArticle number: Dakage this repaig. Metrics details. DNA is subject to constant Pomegranate syrup recipes modification and damage, which eventually Oxidative damage repair in variable mutation rates Liver involvement in glycogen storage disease the genome. Damagge detailed molecular mechanisms Oxiddative DNA damage Maca root for stamina repair are well Oxidarive, damage damagee and execution of repair across a genome remain poorly defined. To bridge the gap between our understanding of DNA repair and mutation distributions, we developed a novel method, AP-seq, capable of mapping apurinic sites and 8-oxo-7,8-dihydroguanine bases at approximately bp resolution on a genome-wide scale. We directly demonstrate that the accumulation rate of apurinic sites varies widely across the genome, with hot spots acquiring many times more damage than cold spots. Unlike single nucleotide variants SNVs in cancers, damage burden correlates with marks for open chromatin notably H3K9ac and H3K4me2.

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Included among these, reactive oxygen Oxidative damage repair ROS Oxidative damage repair as Toddler meal ideas Oxidative damage repair aerobic respiration and Oxidative damage repair give rise to background levels of DNA damage that are reppair when ROS are present in excess 1.

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However, when these mechanisms fail, genomic repaie can lead to disease. DNA damage can xOidative be repari into that caused vamage exogenous factors damagee that which occurs endogenously.

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Causes of endogenous DNA damage include replication errors such as base substitutions or single base insertions; spontaneous base deamination that results in base conversions; and oxidative stress, whereby ROS that are naturally present in cells damage DNA via several different mechanisms 1.

Under normal conditions, ROS are essential to cell growth and survival. For example, by interacting with critical signaling molecules, ROS drive processes including proliferation, apoptosis, and iron homeostasis, while their release from macrophages and neutrophils represents an important defense mechanism against invading pathogens 3,4.

Oxidative DNA damage has been linked to a broad range of diseases and is widely recognized for its contributory role in the initiation and progression of various types of cancer 5,6. StressMarq Biosciences offers a broad portfolio of reagents for studying oxidative DNA damage and its role in disease pathogenesis.

Visit our website to use our interactive graph to explore diseases related to oxidative stressand to see a list of all of our products for studying Oxidative Stress. IHC analysis using Mouse Anti-DNA Damage Monoclonal Antibody, Clone 15A3 SMC Tissue: inflamed colon.

Species: Mouse. Typical Standard Curve for the DNA Damage 8-OHdG ELISA kit SKT Competitive ELISA format, assay range: 0. Your email address will not be published. Save my name, email, and website in this browser for the next time I comment.

What are some types of DNA damage? How is DNA damaged by oxidative stress? What diseases arise from oxidative DNA damage? Advancing understanding of oxidative DNA damage StressMarq Biosciences offers a broad portfolio of reagents for studying oxidative DNA damage and its role in disease pathogenesis.

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: Oxidative damage repair

REVIEW article Tuberculosis Edinb. Additional file 1: Figure S1. Reid, D. Li, H. A reducing agent that reduces disulfide bonds through a thiol—disulfide exchange reaction. Article CAS PubMed Google Scholar Leverrier, P. Cell Commun.
INTRODUCTION

Article PubMed Central Google Scholar. Ting, X. USP11 acts as a histone deubiquitinase functioning in chromatin reorganization during DNA repair. Kuznetsov, N. Pre-steady state kinetics of DNA binding and abasic site hydrolysis by tyrosyl-DNA phosphodiesterase 1.

Poetsch, A. Genomic landscape of oxidative DNA damage and repair reveals regioselective protection from mutagenesis. Genome Biol. Wu, J. Nucleotide-resolution genome-wide mapping of oxidative DNA damage by Click-Code-Seq.

Mao, P. Genome-wide maps of alkylation damage, repair, and mutagenesis in yeast reveal mechanisms of mutational heterogeneity. Genome Res.

Reid, D. Incorporation of a nucleoside analog maps genome repair sites in postmitotic human neurons. Science , 91—94 Wu, W. Neuronal enhancers are hotspots for DNA single-strand break repair. Radulescu, A. NuMA after 30 years: the matrix revisited. Trends Cell Biol. Ohata, H. NuMA is required for the selective induction of p53 target genes.

Jayaraman, S. The nuclear mitotic apparatus protein NuMA controls rDNA transcription and mediates the nucleolar stress response in a pindependent manner. Chang, W. NuMA is a major acceptor of poly ADP-ribosyl ation by tankyrase 1 in mitosis. Altmeyer, M. Liquid demixing of intrinsically disordered proteins is seeded by poly ADP-ribose.

Nair, S. Phase separation of ligand-activated enhancers licenses cooperative chromosomal enhancer assembly. Endo, A. Nuclear mitotic apparatus protein, NuMA, modulates pmediated transcription in cancer cells. Cell Death Dis. Perera, D. Differential DNA repair underlies mutation hotspots at active promoters in cancer genomes.

Janssens, D. zcpf2vn Liu, N. wvgfe3w Cox, J. MaxQuant enables high peptide identification rates, individualized p. Tyanova, S. The Perseus computational platform for comprehensive analysis of prote omics data. Methods 13 , — Li, D. pFind: a novel database-searching software system for automated peptide and protein identification via tandem mass spectrometry.

Bioinformatics 21 , — Wang, L. pFind 2. Rapid Commun. Mass Spectrom. Dobin, A. STAR: ultrafast universal RNA-seq aligner. Bioinformatics 29 , 15—21 Love, M. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Love, I. Differential analysis of count data—the DESeq2 package.

Patro, R. Salmon provides fast and bias-aware quantification of transcript expression. Methods 14 , — Soneson, C. Differential analyses for RNA-seq: transcript-level estimates improve gene-level inferences.

Durinck, S. Giannakakis, A. Contrasting expression patterns of coding and noncoding parts of the human genome upon oxidative stress. Sci Rep.

Quinlan, A. BEDTools: a flexible suite of utilities for comparing genomic features. Bioinformatics 26 , — Sun, Z. Loss of SETDB1 decompacts the inactive X chromosome in part through reactivation of an enhancer in the IL1RAPL1 gene.

Chromatin 11 , 45 Article Google Scholar. Henrich, K. Integrative genome-scale analysis identifies epigenetic mechanisms of transcriptional deregulation in unfavorable neuroblastomas. Cancer Res. Li, H. Fast and accurate long-read alignment with Burrows—Wheeler transform. Sims, D. CGAT: computational genomics analysis toolkit.

Bioinformatics 30 , — Bioinformatics 25 , — Gaspar, J. Improved peak-calling with MACS2. Zerbino, D. Ensembl Liao, Y. featureCounts: an efficient general purpose program for assigning sequence reads to genomic features. Hadley, W. ggplot2: Elegant Graphics for Data Analysis Springer—Verlag, Perez-Riverol, Y.

The PRIDE database and related tools and resources in improving support for quantification data. Download references. We thank L. Ferraiuolo for advice on iPS cell-derived neurons, S. Dumont for providing the hTERT RPE-1 cells containing the stably integrated spCas9 Tet-On promoter and NuMA sgRNA, the Sheffield Wolfson Light Microscopy facility for the imaging experiments and the Sheffield biOMICS Facility for the protein mass spectrometry experiments.

This work was funded by a Wellcome Trust Investigator Award and a Lister Institute of Preventative Medicine Fellowship to S. School of Biosciences, University of Sheffield, Sheffield, UK.

Swagat Ray, Arwa A. Abugable, Jacob Parker, Kirsty Liversidge, Nelma M. Palminha, Chunyan Liao, Cleide D. The Healthy Lifespan and Neuroscience Institutes, University of Sheffield, Sheffield, UK.

Abugable, Nelma M. School of Life and Environmental Sciences, Department of Life Sciences, University of Lincoln, Lincoln, UK. Center for Advanced Parkinson Research, Harvard Medical School, Boston, MA, USA. biOMICS Facility, Faculty of Science Mass Spectrometry Centre, University of Sheffield, Sheffield, UK.

Sheffield Institute of Translational Neuroscience, University of Sheffield, Sheffield, UK. Institute of Cancer Therapeutics, School of Pharmacy and Medical Sciences, University of Bradford, Bradford, UK. You can also search for this author in PubMed Google Scholar.

performed the protein interaction and in vitro transcription experiments. performed the PARylation experiments.

and A. performed the imaging, DNA strand break repair, genome-wide occupancy and oxidative damage experiments. performed all the bioinformatics analyses with advice and support from I. and C. conducted comet assays, in vitro binding and ubiquitination. performed and analysed the protein mass spectrometry experiments.

generated the iPS cell-derived neurons. assisted with the comet assays and performed the cell cycle analysis. A wrote the manuscript. All authors edited the manuscript.

conceived the study, and led and managed the project. Correspondence to Sherif F. Nature thanks Rami Aqeilan, Zhao-Qi Wang and the other, anonymous, reviewer s for their contribution to the peer review of this work.

Expression of TDP1 , XRCC1 and PARP1 across different brain regions in the GTEx v8 dataset. a Immunoblotting of lysates from RPE-1 cells for 4sU-Seq. b A schematic for 4sU-Seq. Log 2 fold changes to KD cells.

g Overlap of genes containing fragile promoters FPG with NRGs. The background set is the total set of differentially expressed genes. In box plots, the centre line is the median, top and bottom hinges show the upper and lower quartiles, and the top and bottom whiskers indicate the largest and smallest values no further than 1.

j Left ; Fold change in nascent RNA transcripts for the indicated SSBR genes. Right ; IGV snapshots of a representative track of the 4sU-Seq profiles of SSBR and DSBR genes. a HEK cells transfected with GFP-empty or GFP-NuMA were treated with H 2 O 2 and recovered for 10 min.

Cell lysates were subjected to GFP-trap immunoprecipitation, on-bead trypsin digestion and subsequent analysis by mass spectrometry. Solid lines indicate significant enrichment of interacting proteins after filtering for a false discovery rate of 0.

Components of the Pol2 and SSBR machineries are highlighted as red squares. b Heat map of clustered proteins identified by mass spectrometry in GFP pull downs.

Hierarchical clustering of LFQ protein intensity shows two dominant sample clusters, GFP and GFP-NuMA-L LTR , according to sample conditions. c HEK cells were treated with either DMSO or inhibitors of PARG PDD , PARP3 ME or PARP1 Olaparib.

d Heat map of clustered proteins identified by mass spectrometry in GFP pull downs. Hierarchical clustering of LFQ protein intensity shows three dominant sample clusters, GFP, GFP-NuMA-S STR and GFP-NuMA-L LTR , according to sample conditions. On the right-hand side, zoomed heat map of NuMA-S STR and NuMA-L LTR intensity profiles across samples.

a A schematic of human NuMA isoforms. b GFP- immunoprecipitates from GFP-NuMA-L and NuMA-S-transfected HEK cells, treated with H 2 O 2 and subjected to mass spectrometric analysis. Annotated tandem mass spectra of NuMA-L top and NuMA-S bottom specific peptides were identified in the immunoprecipitates.

Precursor mass deviation was 2. Due to the extensive DNA damage caused by oxidation, these lesions have been associated with a large number of human maladies including neurodegeneration, cancer and aging 5.

Some of the most widely studied DNA lesions resulting from oxidation are shown in Figure 1. Further oxidation of 8-oxoG results in the formation of spiroiminodihydantoin Sp and 5-guanidinohydantoin Gh.

An important product of thymine oxidation is thymine glycol Tg. Cytosine is subject to methylation, resulting in the formation of 5-methylcytosine 5mC. Oxidative removal of 5-methylcytosine 5mC occurs through an active enzymatic process in which 5mC is oxidized in three steps by a family of TET dioxygenases to form 5-hydroxymethyl-C 5hmC , 5-formylC 5fC and 5-carboxyC 5caC.

Chemical structures of oxidative lesions formed in DNA. A Various oxidation products of guanine. B Formation of cyclic guanosine by oxidation.

C Formation of cyclic adenosine by oxidation. D Enzymatic oxidative demethylation of 5-methylcytosine. E Oxidation of thymine to thymine glycol. ROS produces over different types of lesions in DNA, and this figure displays the structures of those damages that are discussed in this review.

ROS: Reactive oxygen species; DNMT: DNA methyltransferase; TET: Ten-eleven translocation enzymes. Oxidative base lesions are commonly repaired via base excision repair BER pathway 6. BER is initiated after a lesion-specific DNA glycosylase cleaves the glycosidic bond, which frees the lesion, and creates an abasic site 1 Figure 2.

Currently, there are 11 known mammalian DNA glycosylases that can be categorized as monofunctional or bifunctional. This dRP is removed by the lyase activity of DNA polymerase β pol β. The one base gap is then filled by pol β and the nick in the DNA is sealed by DNA ligase 7.

The human 8-oxoG glycosylase OGG1 is a bifunctional glycosylase responsible for the recognition and removal of 8-oxoG. Like several glycosylases, OGG1 is product inhibited, binding avidly to abasic sites, and turns over slowly in the absence of other proteins such as APE1 7. Sp and Gh are removed by the actions of the bifunctional glycosylases Endonuclease VIII-like 1—3 NEIL1—3 , which will be discussed in detail in a later section.

Tg is removed by the bifunctional glycosylase Endonuclease III-like 1 NTHL1. The structures of these glycosylases and their substrates are given in Figure 3. Mammalian base excision repair BER pathway.

The base lesion is excised by a lesion-specific DNA glycosylase. Monofunctional glycosylases break the glycosidic bond between the damaged base and the sugar moiety, resulting in an abasic site. The one base gap is then filled by pol β and the nick in the DNA is sealed by DNA ligase.

Adapted from Kumar et al. BER glycosylases, their structures and respective substrates. The glycosylases green are bound to DNA purple containing a lesion purple, space-filled.

All structures are human except SMUG1 Xenopus laevis , MUTYH Geobacillus stearothermophilus , NEIL2 Monodelphis domestica , NEIL3 Mus musculus , NTHL1 EndoIII, Geobacillus stearothermophilus. PDB: SMUG1 1OE4 , MBD4 5CHZ , UNG 1EMH , TDG 3UFJ , MPG 1BNK , MUTYH 4YOQ , OGG1 1EBM , NEIL1 5ITY , NEIL2 6VJI , NEIL3 3W0F , NTHL1 1ORN.

Abbreviations: U , uracil; A , adenine; T , thymine; C , cytosine; G , guanine; 5-FU , 5-fluorouracil; 5-hmU , 5-hydroxymethyluracil; ϵ , etheno; FaPy , 2,6-diaminohydroxyN-methylformamidopyrimidine; 8-oxoG , 8-oxoguanine; Gh , Guanidonohydantoin; Sp , Spiroiminodihydantonin; Im , iminoallantoin; 5fC , 5-formylcytosine; 5caC , 5-carboxycytosine; 5-BrU , 5-Bromouracil; Tg , Thymine Glycol; meA , 3-methyladenine; meG , 3-methylguanine; 5-hC , 5-hydroxycytosine; 5-hU , 5-hydroxyuracil; 2-hA , 2-hydroxyadenine.

For more than a decade, studies have provided evidence suggesting a role for NER proteins in the repair of oxidative damage through interactions with BER proteins, reviewed 8— NER is the major pathway for the repair of bulky adducts and other helix-distorting lesions, such as UV-induced photoproducts, such as 6—4 photoproducts 6—4 PP and cyclobutane pyrimidine dimers CPD Unlike BER that has a set of glycosylases each tuned to find and process specific altered bases Figure 3 , damage recognition proteins of NER are remarkable in that they have a broad ability to dynamically detect many different structurally and chemically diverse lesions There are two sub-pathways in NER: global-genome NER GG-NER and transcription-coupled NER TC-NER , reviewed in 12 , These sub-pathways differ in the manner of lesion recognition.

In GG-NER, damage recognition proteins scan the entire genome, including heterochromatic, transcriptionally inactive regions, or the non-transcribed strand for damage-induced structural distortions.

In contrast, TC-NER is initiated when RNA polymerase RNAP stalls at damaged site on the transcribed strand of active genes, in euchromatic regions of the genome.

Defects in NER are associated with two important human diseases, xeroderma pigmentosum XP and Cockayne syndrome CS. Damage recognition in GG-NER is initiated by two proteins, UV-DDB and XPC-RAD23B.

In response to UV-induced DNA damage, UV-DDB in complex with CUL4 and RBX forms a ubiquitin E3 ligase complex and binds to the chromatin to ubiquitinate histones, making the lesion more accessible to downstream repair proteins in the NER pathway, including XPC-RAD23B.

XPC-RAD23B binds with high affinity to the strand opposite to the distorted lesion, which begins the damage verification step of NER. XPC-RAD23B facilitates recruitment of the transcription factor TFIIH. TFIIH is a multi-subunit protein, consisting of 10 proteins, including XPB and XPD, proteins that have DNA helicase folds.

When XPD encounters the lesion, its strand opening activity stalls and facilitates the recruitment of XPA, RPA and XPG, collectively known as the pre-incision complex. XPB is believed to act as a translocase to help reel the DNA into the pre-incision complex.

XPA and RPA recruit the heterodimeric endonuclease, XPF-ERCC1. DNA ligase I seals the remaining nick in the repair patch. TC-NER damage recognition is initiated by the presence of a stalled RNAP at a lesion site, which facilitates recruitment of Cockayne syndrome proteins CSB and CSA , and the accessory proteins UVSSA, XAB2, and HMGN1 to the lesion site on the transcribed strand XAB2 facilitates recruitment of XPA and subsequently TFIIH which intertwines the two NER sub-pathways at the damage verification step.

CS patients and a subset of XP patients display signs of neurological degeneration and have been shown to accumulate unrepaired oxidative DNA lesions 16 , Therefore, it is important to understand any crosstalk which exists between the two repair pathways to gain a better understanding of disease progression.

Estimates of cyPu lesions vary, but are generally considered to be less frequent than 8-oxoG, with cdG lesions about an order of magnitude more prevalent that cdA lesions Table 1. As mentioned earlier, defects in NER genes can cause the rare disorder xeroderma pigmentosum XP.

Work by Lindahl's group supported this hypothesis by demonstrating that a subclass of base lesions formed by γ-irradiation were repaired by normal cell extracts, but not by XP cell extracts The first direct evidence of NER involvement in the repair of cyPu lesions was provided by Kuraoka et al.

Therefore, if left unrepaired, cdA lesions can be highly cytotoxic by blocking DNA replication Moreover, when HeLa cell extracts were incubated with 20 bp cdA substrates, no DNA glycosylase-mediated cleavage was observed suggesting that human DNA glycosylases cannot act on cyPu residues.

The excision was significantly suppressed in the presence of an XPA antibody, indicating the dependence of repair on the NER pathway. This study clearly shows that cyPu lesions are removed by NER in vitro , and have the ability to cause local helix distortions and block polymerases.

Brooks et al performed a host reactivation assay HCR in Chinese hamster ovary CHO cells using a plasmid expressing the luciferase Luc gene that contained a cdA lesion on the transcribed strand They showed that a single cdA lesion dramatically decreased the Luc gene expression, suggesting that cdA can act as a strong block to transcription.

They also found that repair of cdA lesion on the plasmid was significantly reduced in XPG and ERCC1 mutant cells as compared to wildtype. They further confirmed this result by employing the HCR assay in SV transformed normal GM and XP-A XP12BE cell lines, providing evidence for defective repair of cdA in the XP-A cells.

The XP12BE cell line was derived from a XP-A patient XP2OS who exhibited severe neurological symptoms Therefore, these studies provide a strong correlation between defective NER and neurodegeneration in XP patients.

In this scenario, an obvious prediction would be that NER deficient XP patients would have elevated levels of cyPu lesions in their DNA. While both normal and XP-C cells accumulated equal numbers of cyPu lesions after 5Gy of X-rays, XP-C cells were inefficient in the removal of damage over time Similar accumulation of cdA was also observed in CSA deficient CS-A fibroblasts treated with X-rays This is consistent with it being a strong transcription blocking lesion as CSA and CSB both recognize DNA damage in the context of transcription.

Further studies are required in more XP and CS patients with neurological disorders to establish a direct link between cyPu accumulation and XP neurodegeneration. Despite the low prevalence of XP throughout the world, it would be of interest to set-up a rapid autopsy program to measure cyPu lesions in brain tissues from deceased XP patients.

Whether cdG lesions could be processed by DNA glycosylases was investigated by Pande et al. In this study, seven purified glycosylases bacterial: Fpg, EndoIII, EndoV, EndoVIII; human: NEIL1, NEIL2, and OGG1 failed to incise a 12 or 36 bp duplex containing a S-cdA or a S-cdG lesion.

Even at high concentrations of the enzymes fmol , no cleavage activity was observed. They also performed binding assays with the glycosylases and found that at very high concentrations 10—20 pmol , NEIL1 bound to both cdA and cdG substrates as well as undamaged DNA, suggesting that the binding was non-specific.

Furthermore, this study went on to demonstrate that S-cdG was repaired slightly better than S-cdA by NER in human HeLa cell extracts and that the base complementary to the lesion affected the efficiency of repair.

They speculated that both base pairing and base stacking are important for the recognition of cyPu lesions in the DNA and that an abnormal Watson-Crick base pairing e.

S-cdG:dT acts as a better substrate for NER. NMR combined with molecular dynamics have proven highly successful in understanding the alterations in the conformation of the DNA helix induced by DNA lesions. It would be of interest to use these techniques to determine the distortions formed on the DNA by the cyPu lesions and investigate the interactions of NEIL1 and other NER recognition proteins with cyPu lesions 33 , Molecular dynamics ns revealed greater DNA backbone distortions and diminished base stacking in the R form of cyPu as compared to the S form.

In cells, DNA lesions are embedded in the nucleosome which can hinder the accessibility of some repair proteins 36— Therefore, to explore the effect of CyPu on histone-DNA interactions, Shafirovich et al.

In both cases, they made the surprising discovery that cyPu lesions were completely resistant to excision by NER proteins in human cell extracts. This suggests that even though cyPu lesions cause significant distortions to naked DNA duplex, they either do not significantly disturb the DNA-histone interactions at these specific positions or these lesions when embedded in a nucleosome escape detection by NER proteins.

It also remains unknown whether these results are relevant in physiological conditions in vivo. It would be, therefore, of great interest to extend these studies to living cells, although there are no tools available yet that could be used to specifically introduce cyPu lesions in cells.

As mentioned earlier, NER proteins recognize and repair UV-induced photoproducts, 6—4 PP and CPD. While a 6—4 PP causes a significant distortion in nucleosomal DNA 48 , a CPD causes less of a distortion It is well-established that while XPC-RAD23B can recognize 6—4PP, this heterodimer has limited ability to detect CPDs, 50 and in cells recruitment of XPC to sites of CPD in chromatin requires UV-DDB.

Furthermore, it is interesting to note that XPC does not efficiently bind DNA configured on a nucleosome On the other hand, UV-DDB has been shown to bind lesions directly in the nucleosome and even shift the nucleosomal register to provide access to more occluded sites 49 , Moreover, the binding of UV-DDB seems to precede the activity of ATP-mediated chromatin remodelers 53 , More recently, as discussed in the last section, our group has demonstrated that the oxidative base damage 8-oxoG, which only causes a mild helix distortion, is recognized by UV-DDB in naked duplex DNA, as well as in living cells 55 , The relatively mild nucleosome distortion caused by CPD and 8-oxoG is analogous to cyPu.

Therefore, it would be interesting to determine the full substrate repertoire of UV-DDB and if UV-DDB is capable of recognizing CyPu and other lesions in the context of nucleosomes. As previously mentioned, during an active enzymatic demethylation process, 5mC is oxidized by TET dioxygenases to 5hmC, 5fC, and 5caC.

The latter two lesions are removed by TDG. TDG has been shown to also remove deaminated 5mC T:G moieties from DNA TDG is a monofunctional glycosylase, which as previously mentioned, binds avidly to abasic sites and thus becomes product inhibited.

Studies have demonstrated roles for other BER proteins, including NEIL1 and APE1 in facilitating TDG turnover. However, the mechanism of DNA demethylation by TDG in cells remains unclear To this end, Ho et al investigated the role of XPC in epigenetic gene regulation through stimulation of TDG.

Using an ELISA specific to 5mC, they were able to show XPC-dependent DNA demethylation This WS XPC variant, discovered in an XP-C patient, XP13PV, was previously shown to have reduced stability in cells, and cells expressing this variant showed reduced rates of removal of UV-induced photoproducts However, careful analysis of data presented in the Ho et al.

In comparison, WT XPC fully doubled the activity of TDG. To provide further support for the role of XPC in TDG stimulation, the authors performed a ChIP-seq analysis and determined co-enrichment of TDG and the XPC subunit, RAD23B at the promoter region of embryonic stem cells.

Additionally, using MeDIP-seq to measure 5mC levels globally in the genome, the authors were able to show reduced DNA methylation in cells overexpressing WT XPC. Single-particle tracking experiments utilizing Halo-tagged TDG and SNAP-tagged XPC, revealed that overexpression of XPC led to a reduction in the length of time Halo-tagged TDG remained bound to DNA.

Using shRNA to knockdown XPC expression the authors demonstrated longer retention of TDG on the DNA. These data support the role of XPC in stimulating TDG activity by facilitating turnover of TDG from the abasic DNA product, Figure 4. Lastly, the authors determined that TDG stimulation by XPC occurs through interactions between the N-terminus of TDG and the C-terminus of XPC.

This study only looked at the role of XPC in TDG stimulation, it would be interesting to determine if any other NER or BER proteins are recruited to the 5mC moiety in response to XPC stimulation.

Thus, further work is needed on the role of XPC, and NER proteins in the oxidative removal of 5mC. XPC and TDG in oxidative demethylation of 5-methylcytosine. Based on the work by Ho et al.

Guanine oxidation is a well-characterized DNA lesion. ROS acting on guanine results in the formation 8-oxoG, through two subtle modifications on guanine Figure 1 : the addition of an oxo group on carbon 8 and the addition of hydrogen to the seventh position nitrogen These modifications causes the base to rotate from the anti- to the syn-conformation with respect to the deoxyribose moiety around the glycosidic bond causing 8-oxoG to pair with A during replication creating T:A transversions, if left unrepaired.

While older literature has referred to this lesion as 8-hydroxy-guanine, this tautomeric form at physiological pH 7. This relatively high lesion frequency of 8-oxoG Table 1 coupled with the implications in genome instability emphasize the need for repair pathways dedicated to the removal of the 8-oxoG lesion.

As mentioned earlier, 8-oxoG is commonly removed through base excision repair BER , through the actions of the DNA glycosylase OGG1. The work by the Mitra laboratory in showing OGG1 is product inhibited and needs the actions of APE1 to facilitate OGG1 turnover, imply the potential for other co-factors outside of BER to stimulate either OGG1 activity or processing of 8-oxoG 7.

The first implications of NER protein involvement in oxidative DNA damage repair was shown using the Escherichia coli NER system consisting of the UvrABC complex The authors used a DNA substrate containing a thymine glycol Tg lesion to show that UvrABC efficiently recognizes and incises the lesion.

This finding was recapitulated in the mammalian system by Sancar and coworkers It has been estimated that the steady-state levels of Tg in mammalian cells are about two orders of magnitude lower than 8-oxoG adducts Table 1.

Using human cell free extracts lacking any one of the XPA-XPG proteins, they were able to show reduced excision of two common oxidative lesions, 8-oxoG and Tg, from damaged DNA substrate Additionally, they showed using a system of purified proteins the need for a complete NER system containing XPC-RAD23B, XPA, RPA, TFIIH XPB and XPD , XPG and XPF-ERCC1, in order for proper excision of 8-oxoG or Tg.

This work from the Sancar laboratory clearly demonstrates the ability of purified NER proteins to remove oxidative lesions, but did not assess whether there was any interaction between NER and BER proteins or whether NER is an important pathway for their removal in cells.

The authors hypothesize the role of NER is to act as a slower alternative pathway for oxidative damage removal by BER, and the loss of this activity in XP patients, contributes to the accumulation of oxidative damage and subsequent neurodegeneration. It is important to point out the ability of the NER machinery to excise 8-oxoG had not been confirmed in any other laboratory or through any other approaches, and it remains to be determined whether NER is a back-up system for the removal of 8-oxoG in the absence of BER.

Following this pioneering work by the Sancar laboratory, which established an in vitro role of NER proteins in oxidative DNA damage repair, attention shifted to understanding the roles of specific NER proteins in the repair of 8-oxoG and other lesions induced by oxidative DNA damage.

Klungland et al began by characterizing the role of XPG in BER of the oxidative lesions, thymine glycol and dihydrouracil. These lesions are excised by the bifunctional DNA glycosylase, NTH1.

Using a reconstituted BER system containing hNTH1, APE1, pol β, and XRCC1-DNA ligase III, the Lindahl laboratory was able to show stimulation of NTH1 by XPG Specifically, they were able to show enhanced binding of NTH1 to damaged DNA in the presence of XPG.

The authors also looked at the ability of XPG to stimulate OGG1 excision of 8-oxoG but were unable to detect any enhanced OGG1 activity in the presence of XPG. In a later study of oxidative damage repair in melanocytes by Wang et al.

cells deficient in XPG protein were shown to have decreased repair of hydrogen peroxide H 2 O 2 -mediated oxidative damage, when measured using a luciferase-based host cell reactivation assay HCR They were also able to show that cells with defective XPA or XPC proteins showed reduced repair of oxidative damage.

Wang et al. went on to further investigate the role of XPA in oxidative DNA damage repair and showed XPA deficient cells had approximately a 4-fold reduction in oxidative damage repair capacity. While this study showed an apparent involvement of NER proteins in the repair of oxidative DNA damage, it remained unclear the specific roles of XPA, XPC and XPG in this process.

The authors hypothesized in the case of melanocytes, the increased presence of melanin which binds to DNA may inhibit the recognition of the damage by both BER and NER proteins. It would be interesting to further investigate whether the levels of melanin prevent recruitment of damage recognition proteins and inhibit subsequent DNA repair.

The Dogliotti lab provided the first evidence of an NER protein, XPC, having a protective role against oxidative stress in human skin cells. Looking at keratinocytes and fibroblasts with a nonsense mutation in the XPC protein, they were able to demonstrate an increased sensitivity to oxidizing damage, such as that from X-rays or potassium bromate, through a colony formation assay While X-rays produce a wide spectrum of DNA lesions including various forms of base damage, single-strand and double-strand breaks, potassium bromide produces primarily 8-oxoG and to a lesser extent other base damages To strengthen support for the role of XPC in oxidative DNA damage repair, they also showed XPC-RAD23B-mediated stimulation of OGG1, the DNA glycosylase responsible for 8-oxoG removal.

They were unable to demonstrate XPA stimulation of OGG1, even at high protein concentrations, even though previous studies alluded to a role for XPA in oxidative damage repair 67 , Furthermore, through far western blot analysis the authors demonstrated a direct binding between OGG1 and XPC-RAD23B, showing XPC enhances the ability of OGG1 to recognize 8-oxoG lesions.

The authors did not show a direct interaction between XPC and damaged DNA, indicating its role is possibly to facilitate the turnover of OGG1. In a later study by the Rainbow lab, XPC deficient fibroblasts were shown to have reduced removal of 8-oxoG Using this reporter gene, they conducted a host cell reactivation assay HCR to investigate the effect of XPC on DNA damage repair.

Additionally, while the authors demonstrated pre-treatment of cells with UVC does not change the relative repair rate of 8-oxoG in XPC-deficient cells, pre-treatment with UVC resulted in an approximate 1. These data imply a potential role of other proteins induced by UV damage mediated through p53 stabilization induced gene expression, in the repair of oxidative damage.

One such protein may be DDB2. Taken together these data suggested BER may not work in isolation to remove oxidative damage. However, the specific molecular roles NER proteins may play in the repair of oxidative damage remained unclear.

To this end, Parlanti et al provided significant insights on the roles of NER proteins, specifically XPA, XPC, CSA, and CSB, on 8-oxoG repair However, all of the NER protein MEF KO cell lines also showed a noticeable reduction in the rates of 8-oxoG repair compared to the WT cells with sufficient NER proteins.

These data suggest CSB and OGG1 are involved in the same repair pathway, one that may be different from that of XPC and XPA. However, the exact molecular details of these pathways remain unresolved. This group were also able to recapitulate the results from the mouse experiments in human XPA fibroblasts, by showing decreased repair of 8-oxoG in addition to increased sensitivity to oxidizing agents.

Using siRNA targeting OGG1 in the XP12SV40 cell line, an XP-A deficient cell line they were able to show impaired repair of 8-oxoG, when compared to XP-A cells or cells with deficient XPC. It remains unclear how the authors were able to demonstrate impaired repair of 8-oxoG in XPA deficient cells in one study, but failed to show XPA-mediated stimulation of OGG1, the glycosylase mediating the repair of the lesion, in another study These conflicting results further reiterates the ambiguity of the role of XPA in 8-oxoG removal, and other published studies show contrasting results The Spivak and Hanawalt laboratory developed a cutting-edge strategy to investigate the role of XPA in repair of relatively low levels of oxidative damage.

Using a comet-FISH combining single-cell gel electrophoresis with a fluorescence in situ hybridization assay , they were able to demonstrate roles for XPA and CSB in the transcription-coupled repair of 8-oxoG In this way the authors were able to show the repair rates of CSB and XPA deficient cells were comparable to the repair rates of the wild-type non-transcribed strand showing the repair of 8-oxoG is coupled to transcription.

To further support the idea of 8-oxoG processing to be coupled to transcription, the authors performed the comet-FISH assay on cells deficient in UVSSA and RNAPII, key proteins in TC-NER, and were able to show that these cells displayed a repair rate similar to that of the wild-type non-transcribed strand.

Finally, they showed that in the absence of OGG1, this transcriptional effect of XPA and CSB was lost, suggesting that RNAP is not inhibited by 8-oxoG, but instead by the resulting SSB created by the actions of OGG1 and APE1. The protective role of XPA was further investigated by the Yasui lab, which utilized the TATAM tracing DNA adducts in the targeted mutagenesis system to study 8-oxoG lesions into XPA knockout cells Introduction of a single 8-oxoG lesion in cells deficient of XPA had no effect on mutagenesis.

Tracks of ionizing radiation can create closely spaced multiple lesions and it was interesting to note that this group was able to show increased mutagenesis in XPA deficient cells with the introduction of multiple 8-oxoG lesions, specifically when the lesions were introduced on the actively transcribed strand.

The Vermeulen lab developed an imaging system to study the roles of NER proteins in 8-oxoG repair. They locally induced 8-oxoG lesions via singlet oxygen by using a photosensitizer and a nm laser CSB and XPC are involved in different sub-pathways of NER, offering an explanation for their different rates of recruitment to damage sites.

In support of a role of CSB in transcription-coupled repair of 8-oxoG, they were able to show enhanced CSB recruitment to the transcriptionally active nucleolus, while XPC was seen more in the heterochromatic nucleoplasm, supporting its role in GG-NER.

This study while demonstrating the recruitment of CSB and XPC to sites of oxidative damage, did not address whether these proteins are directly involved in the removal of 8-oxoG, either through DNA glycosylase stimulation or in some other step in BER.

In a later study, these same authors looked at the role of CSB in 8-oxoG repair by looking at OGG1 recruitment Using the previously described photosensitizer and laser strategy, they induced 8-oxoG lesions and monitored recruitment of CSB and OGG1 to the damage site and demonstrated that CSB recruitment to damage sites is independent of OGG1.

These data seem at odds with the previous work by Spivak and Hanawalt who suggested TCR of 8-oxoG can only occur after processing of the lesion to a strand break.

Furthermore, the Menoni et al. study 77 demonstrated CSB is able to stimulate XRCC1 recruitment to 8-oxoG, in transcriptionally active regions. The authors hypothesize the role of CSB is to aid in the recruitment of XRCC1 and other BER proteins by facilitating chromatin remodeling to aid accessing lesions, especially single-strand breaks.

Additionally, it is important to note that APE1 has been shown to interact directly with CSB and is stimulated up to 6-fold in an ATP-independent manner Thus, CSB may provide an important role during transcription-coupled BER by orchestrating both backtracking of stalled RNAP, as well as coordinating downstream BER proteins.

Finally, it was shown that CSB deficient cells are hypersensitive to killing by hydroxymethyl-deoxyuridine hmdU treatment, suggesting a direct role of CSB in SMUG1-mediated removal of this oxidized base from DNA The oxidation of guanine can create 2,2-diamino[ 2-deoxy-β- d -ery-pentofuranosyl amino -5 2H -oxazolone Oz , and 8-oxoG.

The Oz lesion is normally processed by BER in mammalian cells by the activities of NEIL1 and NTH1 However, using a defined system, Hanaoka and coworkers showed that Oz is also a poor substrate for NER, and that the overall affinity of XPC-RAD23B to a DNA duplex containing Oz was significantly lower than a 6—4 PP containing duplex The 8-oxoG lesion is several orders of magnitude more sensitive to oxidation than the parent guanine moiety resulting in two oxidation products, Sp and Gh, which are less common oxidative lesions, having steady state levels in the range of 0.

These lesions can be removed by BER proteins, however work from several laboratories suggest that NER can also process these lesions.

These results suggest that a larger and more distorting lesion is recognized and incised the most efficiently by the bacterial NER proteins.

Work from the Shavirovich and Geacintov laboratories indicated that human NER proteins from cell extracts can perform dual incisions on Sp or Gh lesions embedded in a bp duplex.

Adding back purified XPC to the latter extract was able to restore NER activity. The same study showed that NEIL1 can also process these lesions in an extract and it was not clear if these two pathways work synergistically or in an antagonistic manner.

This question was elegantly explored in living cells by the same group in which they transfected internally 32 P-labeled DNA hairpin in which the label was placed near the lesion By transfecting this DNA duplex into human cells, they were able to follow the excision of the oligonucleotide containing the lesion via a NER pathway or direct incision by the activity of NEIL1 initiating BER.

They found that compared to a substrate containing a benzo[a]pyrene-dG lesion, Sp or Gh lesions were processed by NER 8- or 6-fold, respectively, less efficiently.

Taken together these data suggested to the authors that the amount of XPC and XPA and perhaps their relatively low affinity for Sp and Gh substrates versus 5—fold higher levels of NEIL1 with high catalytic efficiency in the cell, probably pushes repair of these substrates into a BER pathway.

However, it is not clear whether these transfected DNA hairpins were associated with nucleosomes and what role chromatin structure may play on the processing of Sp and Gh lesions by NER and BER pathways.

Finally, to better explore the question of relative affinities of XPC-RAD23B for Sp and Gh lesions and its ability to compete with NEIL1 for these lesions, the same group studied relative binding affinities of XPC-RAD23 and NEIL for bp duplexes containing Sp or Gh lesions using EMSA analysis They found that XPC-RAD23 bound to Sp containing substrate with high affinity low nM range and that XPC could effectively compete away NEIL1 binding to these substrates at equal molar concentrations.

They then followed NEIL1 incision burst kinetics under single turnover conditions on both substrates in the absence and presence of XPC-RAD23 and found that equal molar concentrations of added XPC-RAD23 greatly reduced the amplitude of the burst phase of NEIL1 cleavage.

Newton, G. Mycothiol biochemistry. Bacillithiol is an antioxidant thiol produced in bacilli. Delaye, L. Molecular evolution of peptide methionine sulfoxide reductases MsrA and MsrB : on the early development of a mechanism that protects against oxidative damage.

Brot, N. Enzymatic reduction of protein-bound methionine sulfoxide. Natl Acad. USA 78 , — This work reports, for the first time, the ability of an Msr enzyme to reduce a methionine sulfoxide in a protein. Rahman, M. Cloning, sequencing, and expression of the Escherichia coli peptide methionine sulfoxide reductase gene.

Grimaud, R. Repair of oxidized proteins. Identification of a new methionine sulfoxide reductase. This study reports the identification of MsrB. Lin, Z. Free methionine- R -sulfoxide reductase from Escherichia coli reveals a new GAF domain function.

USA , — Ezraty, B. Methionine sulfoxide reduction and assimilation in Escherichia coli : new role for the biotin sulfoxide reductase BisC. Kryukov, G. Selenoprotein R is a zinc-containing stereo-specific methionine sulfoxide reductase.

USA 99 , — Sharov, V. Diastereoselective reduction of protein-bound methionine sulfoxide by methionine sulfoxide reductase. FEBS Lett. Moskovitz, J.

Identification and characterization of a putative active site for peptide methionine sulfoxide reductase MsrA and its substrate stereospecificity.

Boschi-Muller, S. The enzymology and biochemistry of methionine sulfoxide reductases. coli methionine sulfoxide reductase with a truncated N terminus or C terminus, or both, retains the ability to reduce methionine sulfoxide. Kumar, R. Reaction mechanism, evolutionary analysis, and role of zinc in Drosophila methionine- R -sulfoxide reductase.

Kim, H. Different catalytic mechanisms in mammalian selenocysteine- and cysteine-containing methionine- R -sulfoxide reductases. PLoS Biol. Russel, M. The role of thioredoxin in filamentous phage assembly. Construction, isolation, and characterization of mutant thioredoxins. Methionine sulfoxide reductase: chemistry, substrate binding, recycling process and oxidase activity.

This review describes the chemistry of Msr enzymes. Lee, T. An anaerobic bacterial MsrB model reveals catalytic mechanisms, advantages, and disadvantages provided by selenocysteine and cysteine in reduction of methionine- R -sulfoxide.

Coudevylle, N. Solution structure and backbone dynamics of the reduced form and an oxidized form of E. coli methionine sulfoxide reductase A MsrA : structural insight of the MsrA catalytic cycle. Ranaivoson, F. A structural analysis of the catalytic mechanism of methionine sulfoxide reductase A from Neisseria meningitidis.

Methionine sulfoxide reductase B displays a high level of flexibility. Lowther, W. The mirrored methionine sulfoxide reductases of Neisseria gonorrhoeae pilB. Mahawar, M. Synergistic roles of Helicobacter pylori methionine sulfoxide reductase and GroEL in repairing oxidant-damaged catalase.

Benoit, S. Alkyl hydroperoxide reductase repair by Helicobacter pylori methionine sulfoxide reductase. Khor, H. Potential role of methionine sulfoxide in the inactivation of the chaperone GroEL by hypochlorous acid HOCl and peroxynitrite ONOO-. Abulimiti, A. Reversible methionine sulfoxidation of Mycobacterium tuberculosis small heat shock protein Hsp Levine, R.

Methionine residues as endogenous antioxidants in proteins. USA 93 , — This study proposes a theory in which methionine residues act as a shield against ROS. Methionine sulfoxide reductases protect Ffh from oxidative damages in Escherichia coli.

This study reports the identification of the SRP54 homologue in bacteria as a target of the MsrAB system through the use of both biochemical and physiological approaches. Luirink, J.

An alternative protein targeting pathway in Escherichia coli : studies on the role of FtsY. Ulbrandt, N. The E. coli signal recognition particle is required for the insertion of a subset of inner membrane proteins.

Cell 88 , — Leverrier, P. Contribution of proteomics toward solving the fascinating mysteries of the biogenesis of the envelope of Escherichia coli. Proteomics 10 , — Silhavy, T. The bacterial cell envelope. Cold Spring Harb.

Depuydt, M. How proteins form disulfide bonds. Bardwell, J. Identification of a protein required for disulfide bond formation in vivo. Cell 67 , — This study describes the identification of DsbA, a protein that catalyses the formation of disulfide bonds in the periplasm.

Bader, M. Oxidative protein folding is driven by the electron transport system. Cell 98 , — Kadokura, H. Detecting folding intermediates of a protein as it passes through the bacterial translocation channel.

Cell , — Shevchik, V. Characterization of DsbC, a periplasmic protein of Erwinia chrysanthemi and Escherichia coli with disulfide isomerase activity. Dutton, R. Bacterial species exhibit diversity in their mechanisms and capacity for protein disulfide bond formation.

This study reveals that there is a bias for an even number of cysteine residues in proteins that are expressed in compartments in which the formation of disulfide bonds occurs. As such, counting the number of cysteine residues can be used to predict whether the formation of disulfide bonds occurs in a specific cellular compartment.

A periplasmic reducing system protects single cysteine residues from oxidation. This paper reports the function of DsbG in the protection of single cysteine residues from oxidation in the periplasm.

Mainardi, J. Unexpected inhibition of peptidoglycan ld-transpeptidase from Enterococcus faecium by the β-lactam imipenem. Denoncin, K. A new role for Escherichia coli DsbC protein in protection against oxidative stress.

Reducing systems protecting the bacterial cell envelope from oxidative damage. Rietsch, A. Reduction of the periplasmic disulfide bond isomerase, DsbC, occurs by passage of electrons from cytoplasmic thioredoxin.

An in vivo pathway for disulfide bond isomerization in Escherichia coli. Katzen, F. Transmembrane electron transfer by the membrane protein DsbD occurs via a disulfide bond cascade. Williamson, J. Structure and multistate function of the transmembrane electron transporter CcdA. Skaar, E.

Olry, A. Characterization of the methionine sulfoxide reductase activities of PilB, a probable virulence factor from Neisseria meningitidis. The thioredoxin domain of Neisseria gonorrhoeae PilB can use electrons from DsbD to reduce downstream methionine sulfoxide reductases.

Saleh, M. Molecular architecture of Streptococcus pneumoniae surface thioredoxin-fold lipoproteins crucial for extracellular oxidative stress resistance and maintenance of virulence. EMBO Mol.

Gennaris, A. Repairing oxidized proteins in the bacterial envelope using respiratory chain electrons. Nature , — This study describes the identification of MsrPQ, which is a widely conserved enzymatic system that protects methionine residues from oxidation in the periplasm.

Brokx, S. Characterization of an Escherichia coli sulfite oxidase homologue reveals the role of a conserved active site cysteine in assembly and function. Biochemistry 44 , — Juillan-Binard, C.

A two-component NADPH oxidase NOX -like system in bacteria is involved in the electron transfer chain to the methionine sulfoxide reductase MsrP. Loschi, L. Structural and biochemical identification of a novel bacterial oxidoreductase.

Melnyk, R. Novel mechanism for scavenging of hypochlorite involving a periplasmic methionine-rich peptide and methionine sulfoxide reductase. mBio 6 , e—15 Characterization of Escherichia coli null mutants for glutaredoxin 2. Kosower, N. Diamide, a new reagent for the intracellular oxidation of glutathione to the disulfide.

Lin, K. Mycobacterium tuberculosis thioredoxin reductase is essential for thiol redox homeostasis but plays a minor role in antioxidant defense. PLoS Pathog. Uziel, O. Transcriptional regulation of the Staphylococcus aureus thioredoxin and thioredoxin reductase genes in response to oxygen and disulfide stress.

Marteyn, B. The thioredoxin reductase—glutaredoxins—ferredoxin crossroad pathway for selenate tolerance in Synechocystis PCC Pasternak, C. Thioredoxin is essential for Rhodobacter sphaeroides growth by aerobic and anaerobic respiration.

Microbiology , 83—91 Scharf, C. Thioredoxin is an essential protein induced by multiple stresses in Bacillus subtilis. CAS PubMed PubMed Central Google Scholar. Navarro, F. The cyanobacterial thioredoxin gene is required for both photoautotrophic and heterotrophic growth.

Plant Physiol. Kuhns, L. Comparative roles of the two Helicobacter pylori thioredoxins in preventing macromolecule damage. Potter, A. Thioredoxin reductase is essential for protection of Neisseria gonorrhoeae against killing by nitric oxide and for bacterial growth during interaction with cervical epithelial cells.

Kraemer, P. Genome-wide screen in Francisella novicida for genes required for pulmonary and systemic infection in mice. Rocha, E. Ortenberg, R. Interactions of glutaredoxins, ribonucleotide reductase, and components of the DNA replication system of Escherichia coli.

Thioredoxin or glutaredoxin in Escherichia coli is essential for sulfate reduction but not for deoxyribonucleotide synthesis. Toledano, M. The system biology of thiol redox system in Escherichia coli and yeast: differential functions in oxidative stress, iron metabolism and DNA synthesis.

Crooke, H. The biogenesis of c -type cytochromes in Escherichia coli requires a membrane-bound protein, DipZ, with a protein disulphide isomerase-like domain. Mavridou, D. The interplay between the disulfide bond formation pathway and cytochrome c maturation in Escherichia coli.

Metheringham, R. Effects of mutations in genes for proteins involved in disulphide bond formation in the periplasm on the activities of anaerobically induced electron transfer chains in Escherichia coli K Beckett, C. Four genes are required for the system II cytochrome c biogenesis pathway in Bordetella pertussis , a unique bacterial model.

Liu, Y. Cytochrome c biogenesis in Campylobacter jejuni requires cytochrome c6 CccA; Cj to maintain apocytochrome cysteine thiols in a reduced state for haem attachment. Braun, M. Cytochrome c maturation and the physiological role of c -type cytochromes in Vibrio cholerae. Page, M. Disruption of the Pseudomonas aeruginosa dipZ gene, encoding a putative protein-disulfide reductase, leads to partial pleiotropic deficiency in c -type cytochrome biogenesis.

Microbiology , — Hiniker, A. Copper stress causes an in vivo requirement for the Escherichia coli disulfide isomerase DsbC. Missiakas, D. Identification and characterization of a new disulfide isomerase-like protein DsbD in Escherichia coli. Crystal structure of the outer membrane protein RcsF, a new substrate for the periplasmic protein-disulfide isomerase DsbC.

Kumar, P. Characterization of DsbD in Neisseria meningitidis. Vertommen, D. The disulphide isomerase DsbC cooperates with the oxidase DsbA in a DsbD-independent manner.

The protein-disulfide isomerase DsbC cooperates with SurA and DsbA in the assembly of the essential β-barrel protein LptD. The Escherichia coli dsbC xprA gene encodes a periplasmic protein involved in disulfide bond formation. An, R. Moraxella osloensis gene expression in the slug host Deroceras reticulatum.

BMC Microbiol. Guo, W. Identification of seven Xanthomonas oryzae pv. oryzicola genes potentially involved in pathogenesis in rice. Vincent-Sealy, L. Erwinia carotovora DsbA mutants: evidence for a periplasmic-stress signal transduction system affecting transcription of genes encoding secreted proteins.

Zhao, C. Role of methionine sulfoxide reductases A and B of Enterococcus faecalis in oxidative stress and virulence.

DNA oxidation - Wikipedia

Examples of exogenous DNA damaging agents include UV radiation that causes covalent linkages to form between adjacent pyrimidines; ionizing radiation IR that generates base lesions and single strand breaks; and chemicals present in tobacco smoke that are converted into alkylating agents able to induce mispairing between bases.

Causes of endogenous DNA damage include replication errors such as base substitutions or single base insertions; spontaneous base deamination that results in base conversions; and oxidative stress, whereby ROS that are naturally present in cells damage DNA via several different mechanisms 1.

Under normal conditions, ROS are essential to cell growth and survival. For example, by interacting with critical signaling molecules, ROS drive processes including proliferation, apoptosis, and iron homeostasis, while their release from macrophages and neutrophils represents an important defense mechanism against invading pathogens 3,4.

Oxidative DNA damage has been linked to a broad range of diseases and is widely recognized for its contributory role in the initiation and progression of various types of cancer 5,6. StressMarq Biosciences offers a broad portfolio of reagents for studying oxidative DNA damage and its role in disease pathogenesis.

Visit our website to use our interactive graph to explore diseases related to oxidative stress , and to see a list of all of our products for studying Oxidative Stress.

IHC analysis using Mouse Anti-DNA Damage Monoclonal Antibody, Clone 15A3 SMC DNA replication is a central process during cell division, where accuracy is essential to maintain the genetic information intact Sancar et al.

However, DNA replication can also be a source of deleterious events leading to DNA damage, in particular, due to aberrant replication fork structures such as breaks associated with replication fork stalling and collapse Zeman and Cimprich, Oxidative stress is also an important source of DNA damage Whitaker et al.

Depending on the source of DNA damage, a specific machinery is activated to promote successful repair Sancar et al. When DNA damage cannot be repaired, cells may undergo programmed cell death or accumulate mutations that drive genomic instability, which can be a trigger for tumorigenesis Hanahan and Weinberg, Even though, dedicated machineries exist to cope with both oxidative stress and DNA damage, when these insults occur, they often lead to a variety of cellular and extracellular changes, which are important to ensure that cells return to their normal physiological equilibrium.

One of these changes is extracellular matrix ECM remodeling. The ECM provides support to tissues and contributes to maintain their appropriate physiological environment Frantz et al. It consists of a network of extracellular glycoproteins e. ECM components can be directly linked to the cell surface and the underlying cytoskeleton, allowing a rapid and precise communication between the cells and the ECM.

The communication between the extracellular and intracellular environments is mediated by transmembrane proteins, such as integrins, syndecans, and dystroglycan Moore and Winder, ; Afratis et al. These transmembrane proteins bind directly to specific domains of ECM molecules on the extracellular side, and to cytoskeletal proteins and different kinases on the intracellular side, thus allowing the transmission of signaling cascades.

In addition, the ECM can also act as a route or reservoir for different molecules with important autocrine and paracrine functions that include cytokines, chemokines, and growth factors, which modulate a variety of different cellular processes, such as cell adhesion, migration, differentiation, proliferation, survival, and apoptosis Bowers et al.

Figure 1. Extracellular matrix ECM remodeling upon oxidative stress and DNA damage. A The ECM is composed of various molecules, such as extracellular glycoproteins e. These components are in close communication with the cell via transmembrane proteins e.

Specific tissues have specialized ECMs and cell surface receptors, as can be observed for skeletal muscle, where the dystrophin-glycoprotein complex anchors laminins and links them to the actin cytoskeleton via dystrophin.

ECM remodeling is carried out through the action of metalloproteinases MMPs and lysyl oxidase LOX. B ECM remodeling can be promoted by oxidative stress. In the presence of increased reactive oxygen species ROS levels [e.

The exact mechanism s by which oxidative stress induces expression of ECM genes remains to be fully uncovered.

The role of oxidative stress is also revealed by treatment with antioxidants where reduction in the levels of ROS normalizes ECM composition. C DNA damage represented as a yellow electric ray symbol on top of double stranded DNA is another insult that triggers changes in the ECM.

The DNA damage responsive protein p53 has been implicated in the downregulation of FN1 expression, promoting cell motility and suppressing apoptosis. Another important player in this context is p This negative regulator of the cell cycle has been shown to induce COL1A1 expression and consequently lead to collagen deposition and fibrosis.

The transcription factor p73, a p53 family member, is also a key protein in ECM remodeling in the response to DNA damage. Upon activation, p73 has been demonstrated to directly promote the transcription of ITGB4 , encoding integrin β4, and consequently promoting cell adhesion.

For simplicity, not all ECM components are shown in the figures, just the ones that are relevant to illustrate the phenomenon being highlighted. Extracellular matrix remodeling is a normal process that occurs during embryonic development, allowing the progressive formation of tissues and organs, and continues throughout adulthood in order to ensure the balance of organismal homeostasis Rozario and DeSimone, ; Bonnans et al.

It is also an important player in tissue healing and repair but, when not properly regulated, it can result in the loss of normal tissue structure and the development of different pathological conditions.

Examples of such conditions are i fibrosis, where extensive ECM deposition and scar formation hamper normal tissue and organ function Herrera et al. Interestingly, diseases characterized by extensive ECM remodeling often involve oxidative stress and DNA damage, either as the triggers or as a consequence of their pathophysiology.

This is the case of the aforementioned pathologies: fibrosis, a pathological condition marked by high levels of oxidative stress and a direct implication of DNA damage Cheresh et al. On the other hand, several diseases due to mutations in ECM components or proteins linking the ECM to the cell cytoskeleton have been shown to display increased oxidative stress and DNA damage in the affected tissues Rando, ; Irwin et al.

This is particularly striking when considering the muscular dystrophies, but other examples also exist. It is essential to point out that ECM remodeling does not only involve the synthesis and deposition of ECM molecules, which transmit signals to cells through cell surface receptors.

The action of specific proteins that degrade ECM components, including metalloproteinases MMPs , and enzymes that shape ECM structure, such as lysyl oxidase LOX , also play a crucial role Bonnans et al. Indeed, the importance of MMPs and their inhibitors, tissue inhibitors of metalloproteinases TIMPs , in the response to oxidative stress and DNA damage has been extensively addressed elsewhere Mehta et al.

We explore studies showing how oxidative stress and DNA damage affect the synthesis of ECM molecules, focusing on the major, and best studied, glycoproteins of the ECM, namely collagens, fibronectin, and laminins Hynes and Naba, ; Naba et al.

We also examine the inverse situation, where mutations in genes encoding some of these key ECM glycoproteins or proteins that link the ECM to the cell cytoskeleton trigger an accumulation of oxidative stress and DNA damage. This dual approach aims to address to what extent oxidative stress and DNA damage are part of the molecular processes that control, and are controlled by, the ECM, and through this perspective, we may deepen our understanding of how they contribute to disease development and progression.

Analysis of NCBI Gene Expression Omnibus database for stress responses in HeLa cells showed that several different forms of stress, including oxidative stress, lead to changes in the expression of genes encoding structural and signaling components of the ECM Chovatiya and Medzhitov, Here, we review the literature reporting when oxidative stress affects the synthesis or structure of the best studied ECM glycoproteins, namely collagens, fibronectin, and laminins.

However, the exact role played by oxidative stress in the regulation of collagen synthesis is still not fully understood, and apparent contradictory results have been described. Siwik et al. This apparent discrepancy might be explained by the amount of oxidative stress in the tissue, as suggested by Liu et al.

In this work, human uterosacral ligament-derived fibroblasts were treated with a low concentration of H 2 O 2 , an important ROS, which led to a decrease in COL1A1 gene codifying for collagen type I α1 chain expression.

In contrast, when these cells were exposed to a higher concentration of H 2 O 2 , their COL1A1 expression increased Liu et al. This suggests that mild oxidative stress, associated with normal metabolism or small insults, may promote the reduction of collagen levels, whereas high levels of oxidative stress may favor collagen accumulation.

Collagen deposition is required for wound healing, but if in excess, can also account for a tissue injury status like fibrosis. In support of this observation, several studies have shown that the presence of elevated levels of oxidative stress lead to increased collagen I and III levels contributing to myocardial fibrosis Zhao et al.

In addition, treatment with antioxidants in the context of cardiac fibrosis has been shown to reduce collagen levels Zhao et al. Glucose deregulation is another mechanism known to cause oxidative stress, as observed for diabetes Yaribeygi et al.

Kidney glomerular mesangial cells cultured with high levels of glucose show increased collagen IV synthesis Ayo et al. Moreover, the synthesis of collagen I and III is increased in hearts of experimental diabetic rats, a condition that was countered by antioxidant treatment Guo et al.

The regulation of collagen synthesis by ROS may not only occur at the transcriptional level. It is well established that the antioxidant vitamin C is a cofactor of prolyl hydroxylase and lysyl hydroxylase, required for post translational modifications of procollagen and consequently in the correct formation of the mature collagen triple helix Frantz et al.

To corroborate the relationship between collagen levels and oxidative stress, it has recently been suggested that vitamin C, due to its role as an antioxidant, could improve healing associated with musculoskeletal diseases, by reducing the levels of ROS associated with the inflammatory response DePhillipo et al.

Even though, pre-clinical studies have shown that vitamin C can reduce ROS and promote tissue healing via collagen I synthesis during bone fracture recovery and in ruptured tendons, more studies in a clinical setting are needed to assess its therapeutic benefit DePhillipo et al.

The expression or stability of fibronectin has also been linked to oxidative stress. Fibronectin FN1 expression has been shown to be positively regulated in the presence of different sources of oxidative stress Iglesias-De La Cruz et al. Oxidative stress, due to high glucose levels, increases the expression of FN1 in vitro Ayo et al.

ROS reduction by treatment with the ROS scavenging enzyme superoxide dismutase SOD led to a reduction in fibronectin levels in diabetic rats and to less kidney damage Lin et al. Furthermore, HOCl generated through MPO activity in neutrophils has been shown to induce fibronectin modifications, such as tyrosine chlorination and dichlorination and oxidation of different residues, which reduced cell adhesion and increased proliferation of human coronary artery smooth muscle cells in vitro Nybo et al.

The HOCl-induced modifications of fibronectin also led to changes in the expression of ECM genes by these smooth muscle cells, including a significant upregulation of FN1 and LAMA1 and downregulation of LAMB2 expression Nybo et al.

LAMA1 codifies the laminin α1 chain, which is normally not present in the basement membrane of smooth muscle cells, while downregulation of LAMB2 codifying the laminin β2 chain indicates that cells are prevented from maintaining β2 laminins, characteristic of mature smooth muscle basement membranes Yousif et al.

These data indicate that cells attempt to remodel their ECM in response to their oxidant-altered fibronectin substrate and associated effects on cell adhesion and proliferation.

Altogether, these various studies show that oxidative stress causes changes in both ECM gene expression and in ECM structure which correlate with tissue damage. It is well established that DNA integrity is essential for gene expression and for the correct transmission of genetic information to daughter cells during mitosis.

It is not surprising that DNA damage is one of the most deleterious forms of injury inflicted on cells Sancar et al. Here, we will consider how DNA damage, independently of the source e. A central protein involved in the DNA damage response is the tumor suppressor p53, which, when activated, either induces cell cycle arrest to allow for DNA repair or, if the damage inflicted is too large, promotes, for example, apoptosis Sancar et al.

p53 has been implicated in the regulation of FN1 expression. Depletion of p53 was shown to increase FN1 mRNA expression, leading to increased cell motility and decreased apoptosis Yokoi et al. These studies thus indicate p53 as a negative regulator of FN1 expression.

In accordance with this notion, overexpression of wild type p53 in ovarian carcinoma cells was able to repress the activity of the FN1 promoter, while a mutant p53 failed to do so Yokoi et al.

Another indication of an effect of DNA damage on the expression of ECM components came from a study on the CDK inhibitor p21 Yosef et al.

This study revealed that in p21 knockout mice, senescent cells were eliminated, and liver fibrosis was alleviated mainly via transcriptional downregulation of collagen type I α1 COL1A1 ; Yosef et al. In fact, p21 knockout reduced Col1a1 expression, prevented collagen deposition and consequently fibrosis, in mice treated with carbon tetrachloride, a fibrogenic agent known to cause DNA damage Yosef et al.

These observations suggest that one of the actions of p21 is to increase COL1A1 expression in response to DNA damage. However, further studies are needed to assess whether these described effects of p53 and p21 on FN1 and COL1A1 expression, respectively, are cell type specific and exactly how the pathways involved control cell survival, senescence, and apoptosis.

Integrins provide yet another link between ECM structure and DNA damage-induced apoptosis Hoyt et al. Nevertheless, the connection between adhesion and apoptosis is not linear and integrin binding to the ECM can either promote or prevent cells, in particular cancer cells, from undergoing apoptosis.

It is possible that regulation mediated by factors involved in the DNA damage response, such as p53 and p21, control the expression of integrins or ECM components and therefore modulate adhesion.

Indeed, it has been shown that p73, a p53 family member that can also be activated in response to DNA damage, directly promotes transcription of ITGB4 , encoding integrin β4, therefore acting as a positive regulator of cell adhesion Xie et al.

Collectively, this suggests that central DNA damage response factors might be able to directly control the expression of ECM components and integrins, hence being able to regulate cell survival and apoptosis. As discussed above, the notion that oxidative stress and DNA damage result in alterations in the ECM in the context of different diseases has been gaining ground.

However, does the inverse occur? Does a dysfunctional ECM induce oxidative stress and DNA damage in the cells it harbors? Indeed, some observations suggest that this is the case.

For example, culture of human dermal fibroblasts in fragmented collagen matrices, resulted in elevated levels of ROS in these cells compared to fibroblasts cultured in intact collagen matrices Fisher et al.

Collagen I is present in a variety of connective tissues Frantz et al. Mutations in COL1A1 and COL1A2 genes, encoding the α1 and α2 chains of collagen I, respectively, cause osteogenesis imperfecta, a disease characterized by brittle bones, short stature, and muscle weakness van Dijk et al.

Moreover, excessive ROS production in the context of collagen I deficiency may also contribute to the exacerbation of osteogenesis imperfecta pathology in bone. Indeed, high ROS generation is associated with inhibition of new bone formation, suggesting that antioxidant treatment may be useful to treat diseases with bone loss Wauquier et al.

Figure 2. Mutations in ECM components increase oxidative stress. Many diseases caused by mutations in ECM components or components that link ECM to the cytoskeleton have been associated with generation of excess ROS levels. The loss of collagen I, collagen VI, laminin α2, or dystrophin was shown to induce mitochondrial dysfunction, a major source of ROS.

Additionally, high ROS levels due to either increased activity of monoamine oxidase A MAO-A or NADPH oxidase have also been associated with the loss of specific ECM or ECM-related components. Loss of laminin α2 or dystrophin leads to increased levels of ROS as a consequence of the activation of inflammatory cells.

Dystrophin loss was also shown to promote changes in the activity of antioxidant pathways and ROS-induced DNA damage. Collagen VI is a type of collagen mainly found in muscles, tendons, and skin Bönnemann, Mutations in the COL6A1 , COL6A2 , and COL6A3 genes, encoding chains of collagen VI, are associated with Ullrich congenital muscular dystrophy and Bethlem myopathy, a severe and mild form of collagen VI deficiency, respectively Bönnemann, ; Bernardi and Bonaldo, Collagen VI deficiency has also been correlated with oxidative stress.

Consistent with this, treatment with a MAO inhibitor Menazza et al. Altogether, these studies reinforce the idea that the absence of collagen VI drives excess ROS production in the mitochondria, potentially contributing to the observed muscle fiber damage.

The LAMA2 gene encodes the laminin α2 chain of laminin Mutations in LAMA2 lead to a congenital muscular dystrophy LAMA2-CMD; also known as merosin-deficient congenital muscular dystrophy type 1A, MDC1A which is characterized by muscle weakness, fibrosis, and chronic inflammation Gawlik and Durbeej, ; Yurchenco et al.

These studies indicate that the muscles of Lama2 -deficient mice and LAMA2-CMD patients display an increase in oxidative stress both in early and more advanced stages of the disease, pointing to an important role of oxidative stress throughout disease progression Gawlik et al.

Vitamin E, another antioxidant, applied to the same mouse model reduced the number of apoptotic fibers and attenuated inflammation in quadriceps muscles, although, it did not improve motor function or reduce fibrosis Harandi et al.

Mitochondrial dysfunction, closely associated with elevated oxidative stress, also plays a central role in LAMA2-CMD pathology. In fact, it was observed that Lama2 -deficient mice present signs of mitochondrial swollenness Millay et al.

Likewise, muscles or muscle-derived cells from LAMA2-CMD patients were described as having an abnormal membrane potential Fontes-Oliveira et al. Altogether, these results support the hypothesis that oxidative stress and mitochondrial dysfunction are hallmarks of LAMA2-CMD.

Dystrophin is part of the dystrophin-glycoprotein complex which links cytoplasmic dystrophin to laminin in the muscle fiber basement membrane, a link that is responsible for conferring cellular stability during skeletal muscle contractions Ervasti and Campbell, Mutations in the DMD gene, encoding dystrophin, can cause Duchenne muscular dystrophy DMD , characterized by muscle weakness, inflammation, and fibrosis Grounds et al.

Several mechanisms are known to contribute to DMD pathology, including oxidative stress Rando, ; Grounds et al.

Early studies of the disease showed that DMD muscles display oxidative stress features, such as increased lipid peroxidation Hunter and Mohamed, and increased levels of oxidative stress responsive enzymes Austin et al.

Moreover, in vivo and in vitro analyzes of mdx mice, the most widely used DMD model, showed an increased susceptibility to muscle injury caused by free radicals Disatnik et al. During the last decades, the oxidative stress hypothesis has been gathering support with several studies showing high levels of ROS in muscles of mdx mice Ragusa et al.

The excessive production of ROS in DMD patients and mdx mice may have multiple sources, including activation of inflammatory cells Whitehead et al. Using antioxidizing drugs, such as vitamin C or SOD, and treatment with the antioxidant NAC reduced the levels of ROS in cardiac Williams and Allen, and skeletal muscles Whitehead et al.

It also reduced the expression of markers of inflammation and fibrosis Williams and Allen, , as well as, the number of apoptotic fibers Whitehead et al. This observed rescue of the DMD phenotype using antioxidant treatments suggests a possible role of ROS in the inflammation, fibrosis, and apoptosis characteristic of DMD.

Elevated levels of NADPH oxidase and its regulator caveolin-3 is also a hallmark of mdx muscles Williams and Allen, ; Whitehead et al. NADPH oxidase produced in skeletal muscles fibers has been shown to be a major source of stretch-induced ROS in mdx mice Shkryl et al. Furthermore, NAC treatment reduced caveolin-3 expression and NF-κB activation in skeletal muscles from mdx mice Whitehead et al.

Another important player in DMD pathology is mitochondrial dysfunction Menazza et al. Elevated levels of MAO were reported in mdx mice Menazza et al. Inhibition of MAO reduced tropomyosin oxidation an oxidation marker , normalized fiber size, and reduced tissue inflammation and apoptosis Menazza et al.

Reactive oxygen species pose various risks for the integrity of different macromolecules including DNA. In keeping with this notion, DMD patients present high levels of DNA damage associated with increased oxidative stress Rodriguez and Tarnopolsky, and cells derived from DMD patients are more sensitive to DNA-damaging agents than control cells Robbins et al.

More recently, Jelinkova et al. Although, the precise mechanisms and direct or indirect actions and targets are not yet clarified, all these studies sustain the notion that mutations in the genes encoding ECM components, or associated proteins, may trigger oxidative stress and DNA damage.

Importantly, some studies, especially those focusing on muscular dystrophies, have raised the question whether oxidative stress constitutes a primary or a secondary event in disease progression Rando, ; Moore et al. In most cases, studies are conducted during the active phase of the disease, making it impossible to distinguish between these two events.

Thus, in the context of mutations in genes encoding ECM components or proteins that link the ECM to cytoskeleton, it is unclear whether oxidative stress acts as a cause, a consequence or both, of disease progression. Hence, more studies are needed to fully understand how oxidative stress contributes to each phase of the disease.

Taking into account the link between oxidative stress and DNA damage, it is likely that oxidative stress induced DNA damage may not be limited to DMD Robbins et al. The concomitant presence of oxidative stress and DNA damage can act as an important driving force for disease progression.

Therefore, understanding the exact mechanisms behind the accumulation of oxidative stress in each phase of these diseases and determining the cellular consequences of increased ROS in every phase is crucial to design targeted therapies for these devastating conditions.

The ECM is an intricate network of different molecules that communicate directly to the intracellular space through cell surface receptors and downstream signaling cascades. It is becoming increasingly clear that altered expression of one of these molecules may perturb this fine-tuned communication, triggering a domino effect, which severely compromises tissue integrity.

In this review, we examined several examples, where increased oxidative stress and DNA damage alter the expression of genes encoding key ECM components, and conversely, where mutations in genes encoding some of the best studied ECM glycoproteins and proteins linking the ECM to the cell cytoskeleton elicit an increase in oxidative stress and DNA damage.

The crosstalk between these two processes, and their major impact on tissue integrity and function, highlights the necessity to study the molecular nature of this relationship further, opening the possibility of identifying new candidate pathways as targets for therapy.

In response to oxidative stress and DNA damage, regulation of ECM remodeling may occur at different levels, including i transcriptional, via modulation of different transcription factors, ii posttranslational, by the action of MMPs, TIMPs, and LOX, which control the degradation of ECM components, and iii at the network level, where changes in an ECM components or molecules that bridge the ECM to the cell cytoskeleton, may trigger a chain reaction that can compromise tissue integrity.

Here, we discuss how oxidative stress and DNA damage could influence or be influenced by the expression of genes encoding ECM components or proteins linking to the cell cytoskeleton and dissect out which pathways may be required for this regulation. TGF-β signaling is one of the key regulators of ECM production Hinz, ; Tu and Quan, , via the activation of Smad transcription factors, which regulate the transcription of ECM genes Figure 3A , for example, collagens and fibronectin, but also ECM proteolytic enzymes, such as MMPs Tu and Quan, In particular, induction of TGF-β signaling by oxidative stress has been associated with increased transcription of collagens and fibronectin Iglesias-De La Cruz et al.

Another study, points to the activation of the TNF pathway as important for the transcription of collagen I and III genes, in response to angiotensin II-induced oxidative stress Sriramula and Francis, , possibly via the activation of the NF-κβ transcription factor Morgan and Liu, NF-κβ is also activated in response to DNA damage Janssens and Tschopp, , leading to the transcription of several targets, including ECM related genes Janssens and Tschopp, ; Guo et al.

NRF2 is another important orchestrator of the oxidative stress response and which acts as a transcription factor He et al. This important stress sensor has been shown to be required for the transcriptional regulation of several matrisome genes, including collagen I, III, and laminin α1 chain genes Hiebert et al.

As mentioned above, the transcriptional regulation of ECM components may also be mediated directly or indirectly via the transcription factors p53 and p73, both playing important roles sensing oxidative stress and DNA damage Holmstrom et al.

Whether these candidate pathways and transcription factors, known to regulate the expression of ECM genes, act in a tissue or disease specific manner, remains to be further explored.

Figure 3. Oxidative stress and DNA damage links to ECM remodeling. A Oxidative stress and DNA damage may trigger ECM remodeling by different mechanisms. One possible mechanism is associated with ROS-mediated release of TGFβ from the large latent complex, allowing it to bind to the TGFβ receptor 1.

This promotes the activation of the SMAD transcriptional complex, known to promote transcription of ECM genes. Another possible mechanism involves the activation of the NF-κβ transcription factor 2.

This may occur in the presence of oxidative stress leading to NF-κβ mediated transcription of TNFα, which in turn further promotes NF-κβ activation and transcriptional regulation of ECM genes.

NF-κβ can also be activated by DNA damage and control the transcription of ECM target genes. The oxidative stress sensor nuclear factor erythroid 2-related factor 2 NRF2; 3 , may also have a crucial role in the transcriptional regulation of ECM genes.

The transcription factors p53 and p73, which regulate ECM gene expression, are both known targets of oxidative stress and DNA damage 4. B ECM stability is important to prevent the generation of oxidative stress and DNA damage. The integrin-focal adhesion kinase FAK pathway promotes mitochondrial function, via phosphorylation of STAT3, which is implicated in the reduction of ROS and maintenance of mitochondrial membrane potential 1.

Biomechanical properties of the ECM are also critical to maintain cell structure 3. An appropriate ECM stiffness maintains mitochondrial dynamics, possibly preventing ROS production, and nuclear structure, supporting genomic integrity and avoiding DNA damage.

Dashed lines represent pathways that may involve one or more intermediate players. As detailed earlier, several studies point to oxidative stress and DNA damage being a consequence, rather than a cause, of changes in the ECM.

In line with this, mutations in genes encoding ECM components or molecules that bridge the ECM to the cell cytoskeleton have been described to lead to mitochondrial dysfunction Irwin et al. There are several different mechanisms that can explain why mitochondria may function as an important sensor for ECM changes De Cavanagh et al.

ECM glycoproteins, including laminins and fibronectin, have been shown to promote mitochondrial function via integrin-focal adhesion kinase FAK signaling, which culminates in the translocation of phosphorylated STAT3 to the mitochondria Visavadiya et al.

Other possible mechanisms are related to the loss of adhesion to the ECM, which changes the cellular uptake of nutrients, namely glucose Schafer et al. These effects together with the reduction in the activity of phosphatidyl-inositolkinase PI3K and Akt, also associated with altered ECM composition, elicits dramatic metabolic changes including decreased activity of the pentose phosphate pathway, which represents an important source of NADPH, a powerful antioxidant molecule Eble and De Rezende, ; Figure 3B.

In addition to signaling pathways linking ECM to mitochondria, biomechanical properties of the ECM, such as stiffness i. High ECM stiffness has been shown to promote mitochondrial fusion and suppress mitochondrial fission downstream of integrin signaling Chen et al.

The importance of ECM biomechanical properties goes beyond maintaining mitochondrial stability. Low ECM stiffness compromises the DNA damage response, making cells more sensitive to DNA damaging agents Deng et al.

Altogether, these studies suggest that countering mitochondrial dysfunction, and possibly preventing DNA damage, may be a promising strategy to revert the pathology caused by some mutations in genes encoding ECM components, their receptors or molecules that bridge ECM receptors to the cell cytoskeleton.

The article 8-oxo-2'-deoxyguanosine refers to the same damaged base since the keto form 8-oxo-Gua described there may undergo a tautomeric shift to the enol form 8-OH-Gua shown here. The other product was FapyGua 2,6-diaminohydroxyformamidopyrimidine.

Another frequent oxidation product was 5-OH-Hyd 5-hydroxyhydantoin derived from cytosine. Most oxidized bases are removed from DNA by enzymes operating within the base excision repair pathway. For example, 8-oxo-dG was increased fold in the livers of mice subjected to ionizing radiation, but the excess 8-oxo-dG was removed with a half-life of 11 minutes.

Steady-state levels of endogenous DNA damages represent the balance between formation and repair. Swenberg et al. The seven most common damages they found are shown in Table 1. Only one directly oxidized base, 8-hydroxyguanine , at about 2, 8-OH-G per cell, was among the most frequent DNA damages present in the steady-state.

As reviewed by Valavanidis et al. They also noted that increased levels of 8-oxo-dG are frequently found associated with carcinogenesis and disease.

In the figure shown in this section, the colonic epithelium from a mouse on a normal diet has a low level of 8-oxo-dG in its colonic crypts panel A.

However, a mouse likely undergoing colonic tumorigenesis due to deoxycholate added to its diet [10] has a high level of 8-oxo-dG in its colonic epithelium panel B.

Deoxycholate increases intracellular production of reactive oxygen resulting in increased oxidative stress, [12] [13] and this may contribute to tumorigenesis and carcinogenesis. Valavanidis et al. The first mechanism involves modulation of gene expression, whereas the second is through the induction of mutations.

Epigenetic alteration, for instance by methylation of CpG islands in a promoter region of a gene, can repress expression of the gene see DNA methylation in cancer. In general, epigenetic alteration can modulate gene expression.

As reviewed by Bernstein and Bernstein, [14] the repair of various types of DNA damages can, with low frequency, leave remnants of the different repair processes and thereby cause epigenetic alterations. Nishida et al. These biopsies were taken from patients with chronic hepatitis C, a condition causing oxidative damages in the liver.

This promoter methylation could have reduced expression of these tumor suppressor genes and contributed to carcinogenesis. Yasui et al. They inserted 8-oxo-dG into about cells, and could detect the products that occurred after the insertion of this altered base, as determined from the clones produced after growth of the cells.

G:C to T:A transversions occurred in 5. Together, these more common mutations totaled 9. Among the other mutations in the clones analyzed, there were also 3 larger deletions, of sizes 6, 33 and base pairs.

Thus 8-oxo-dG, if not repaired, can directly cause frequent mutations, some of which may contribute to carcinogenesis. As reviewed by Wang et al.

As noted by Wang et al. They then described three modes of gene regulation by DNA oxidation at guanine. In one mode, it appears that oxidative stress may produce 8-oxo-dG in a promoter of a gene.

The oxidative stress may also inactivate OGG1. The inactive OGG1, which no longer excises 8-oxo-dG, nevertheless targets and complexes with 8-oxo-dG, and causes a sharp ~70 o bend in the DNA.

This allows the assembly of a transcriptional initiation complex, up-regulating transcription of the associated gene. The experimental basis establishing this mode was also reviewed by Seifermann and Epe [20]. A third mode of gene regulation by DNA oxidation at a guanine, [19] occurs when 8-oxo-dG is complexed with OGG1 and then recruits chromatin remodelers to modulate gene expression.

Chromodomain helicase DNA-binding protein 4 CHD4 , a component of the NuRD complex, is recruited by OGG1 to oxidative DNA damage sites. CHD4 then attracts DNA and histone methylating enzymes that repress transcription of associated genes.

Seifermann and Epe [20] noted that the highly selective induction of 8-oxo-dG in the promoter sequences observed in transcription induction may be difficult to explain as a consequence of general oxidative stress.

However, there appears to be a mechanism for site-directed generation of oxidized bases in promoter regions. Perillo et al. As a specific example, after treatment of cells with an estrogen, LSD1 produced H 2 O 2 as a by-product of its enzymatic activity.

The oxidation of DNA by LSD1 in the course of the demethylation of histone H3 at lysine 9 was shown to be required for the recruitment of OGG1 and also topoisomerase IIβ to the promoter region of bcl-2 , an estrogen-responsive gene, and subsequent transcription initiation.

In mouse embryonic fibroblasts , a 2 to 5-fold enrichment of 8-oxo-dG was found in genetic control regions, including promoters , 5'-untranslated regions and 3'-untranslated regions compared to 8-oxo-dG levels found in gene bodies and in intergenic regions.

Oxidative stress, protein damage and repair in bacteria | Nature Reviews Microbiology

XRCC1 stimulates human polynucleotide kinase activity at damaged DNA termini and accelerates DNA single-strand break repair. Cell , — A requirement for PARP-1 for the assembly or stability of XRCC1 nuclear foci at sites of oxidative DNA damage. Das, B. PARP1—TDP1 coupling for the repair of topoisomerase I-induced DNA damage.

Awwad, S. NELF-E is recruited to DNA double-strand break sites to promote transcriptional repression and repair. EMBO Rep. Hoch, N. XRCC1 mutation is associated with PARP1 hyperactivation and cerebellar ataxia. Nature , 87—91 Takashima, H. Mutation of TDP1, encoding a topoisomerase I—dependent DNA damage repair enzyme, in spinocerebellar ataxia with axonal neuropathy.

Giampetruzzi, A. Modulation of actin polymerization affects nucleocytoplasmic transport in multiple forms of amyotrophic lateral sclerosis. Article ADS PubMed PubMed Central Google Scholar. Maynard, S. CAS PubMed PubMed Central Google Scholar.

Lydersen, B. Cell 22 , — Hueschen, C. NuMA recruits dynein activity to microtubule minus-ends at mitosis. eLife 6 , e Article PubMed PubMed Central Google Scholar. Merdes, A. A complex of NuMA and cytoplasmic dynein is essential for mitotic spindle assembly.

Cell 87 , — The role of NuMA in the interphase nucleus. Cell Sci. Vidi, P. NuMA promotes homologous recombination repair by regulating the accumulation of the ISWI ATPase SNF2h at DNA breaks. Salvador-Moreno, N. The nuclear structural protein NuMA is a negative regulator of 53BP1 in DNA double-strand break repair.

Serra-Marques, A. The mitotic protein NuMA plays a spindle-independent role in nuclear formation and mechanics. Bahrami, S. Gene regulation in the immediate—early response process.

Tullai, J. Immediate—early and delayed primary response genes are distinct in function and genomic architecture. Samson, L. A target to suppress inflammation. Science , — Visnes, T.

Small-molecule inhibitor of OGG1 suppresses proinflammatory gene expression and inflammation. Dellino, G. Release of paused RNA polymerase II at specific loci favors DNA double-strand-break formation and promotes cancer translocations. Google Scholar. Boehler, C. Poly ADP-ribose polymerase 3 PARP3 , a newcomer in cellular response to DNA damage and mitotic progression.

Chang, P. Tankyrase-1 polymerization of poly ADP-ribose is required for spindle structure and function. Haren, L. Direct binding of NuMA to tubulin is mediated by a novel sequence motif in the tail domain that bundles and stabilizes microtubules.

Hendriks, I. An advanced strategy for comprehensive profiling of ADP-ribosylation sites using mass spectrometry-based proteomics. Cell Proteomics 18 , — Palazzo, L. Serine is the major residue for ADP-ribosylation upon DNA damage.

eLife 7 , e Páhi, Z. PARylation during transcription: insights into the fine-tuning mechanism and regulation. Cancers 12 , Article PubMed Central Google Scholar. Ting, X. USP11 acts as a histone deubiquitinase functioning in chromatin reorganization during DNA repair. Kuznetsov, N.

Pre-steady state kinetics of DNA binding and abasic site hydrolysis by tyrosyl-DNA phosphodiesterase 1. Poetsch, A. Genomic landscape of oxidative DNA damage and repair reveals regioselective protection from mutagenesis.

Genome Biol. Wu, J. Nucleotide-resolution genome-wide mapping of oxidative DNA damage by Click-Code-Seq. Mao, P. Genome-wide maps of alkylation damage, repair, and mutagenesis in yeast reveal mechanisms of mutational heterogeneity.

Genome Res. Reid, D. Incorporation of a nucleoside analog maps genome repair sites in postmitotic human neurons. Science , 91—94 Wu, W. Neuronal enhancers are hotspots for DNA single-strand break repair. Radulescu, A. NuMA after 30 years: the matrix revisited.

Trends Cell Biol. Ohata, H. NuMA is required for the selective induction of p53 target genes. Jayaraman, S. The nuclear mitotic apparatus protein NuMA controls rDNA transcription and mediates the nucleolar stress response in a pindependent manner.

Chang, W. NuMA is a major acceptor of poly ADP-ribosyl ation by tankyrase 1 in mitosis. Altmeyer, M. Liquid demixing of intrinsically disordered proteins is seeded by poly ADP-ribose. Nair, S. Phase separation of ligand-activated enhancers licenses cooperative chromosomal enhancer assembly.

Endo, A. Nuclear mitotic apparatus protein, NuMA, modulates pmediated transcription in cancer cells. Cell Death Dis. Perera, D. Differential DNA repair underlies mutation hotspots at active promoters in cancer genomes.

Janssens, D. zcpf2vn Liu, N. wvgfe3w Cox, J. MaxQuant enables high peptide identification rates, individualized p. Tyanova, S. The Perseus computational platform for comprehensive analysis of prote omics data. Methods 13 , — Li, D.

pFind: a novel database-searching software system for automated peptide and protein identification via tandem mass spectrometry.

Bioinformatics 21 , — Wang, L. pFind 2. Rapid Commun. Mass Spectrom. Dobin, A. STAR: ultrafast universal RNA-seq aligner. Bioinformatics 29 , 15—21 Love, M. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2.

Love, I. Differential analysis of count data—the DESeq2 package. Patro, R. Salmon provides fast and bias-aware quantification of transcript expression. Methods 14 , — Soneson, C.

Differential analyses for RNA-seq: transcript-level estimates improve gene-level inferences. Durinck, S. Giannakakis, A. Contrasting expression patterns of coding and noncoding parts of the human genome upon oxidative stress. Sci Rep.

Quinlan, A. BEDTools: a flexible suite of utilities for comparing genomic features. Bioinformatics 26 , — Sun, Z. Loss of SETDB1 decompacts the inactive X chromosome in part through reactivation of an enhancer in the IL1RAPL1 gene. Chromatin 11 , 45 Article Google Scholar.

Henrich, K. Integrative genome-scale analysis identifies epigenetic mechanisms of transcriptional deregulation in unfavorable neuroblastomas. Cancer Res. Li, H. Fast and accurate long-read alignment with Burrows—Wheeler transform.

Sims, D. CGAT: computational genomics analysis toolkit. Bioinformatics 30 , — Bioinformatics 25 , — Gaspar, J. Improved peak-calling with MACS2. Zerbino, D. EMBO J. Traore, D. et al. Structural and functional characterization of 2-oxo-histidine in oxidized PerR protein.

Feeney, M. Tyrosine modifications in aging. Thurlkill, R. p K values of the ionizable groups of proteins.

Protein Sci. Thiol chemistry and specificity in redox signaling. Nagy, P. Kinetics and mechanisms of thiol—disulfide exchange covering direct substitution and thiol oxidation-mediated pathways. Paulsen, C. Cysteine-mediated redox signaling: chemistry, biology, and tools for discovery.

Roos, G. Protein sulfenic acid formation: from cellular damage to redox regulation. Cellular defenses against superoxide and hydrogen peroxide. Davies, M. The oxidative environment and protein damage. Acta , 93— Lavine, T. The formation, resolution, and optical properties of the diastereoisomeric sulfoxides derived from L -methionine.

CAS PubMed Google Scholar. Lee, B. The biological significance of methionine sulfoxide stereochemistry. Vogt, W. Oxidation of methionyl residues in proteins: tools, targets, and reversal. Schoneich, C. Methionine oxidation by reactive oxygen species: reaction mechanisms and relevance to Alzheimer's disease.

Acta , — Buxton, G. Critical review of rate constants for reactions of hydrated electrons, hydrogen atoms and hydroxyl radicals in aqueous solution. Data 17 , — Article CAS Google Scholar.

Pattison, D. Absolute rate constants for the reaction of hypochlorous acid with protein side chains and peptide bonds. Padmaja, S. Rapid oxidation of DL -selenomethionine by peroxynitrite. Collet, J. Structure, function, and mechanism of thioredoxin proteins. Arts, I. Comprehensively characterizing the thioredoxin interactome in vivo highlights the central role played by this ubiquitous oxidoreductase in redox control.

Proteomics 15 , — Thioredoxin 2, an oxidative stress-induced protein, contains a high affinity zinc binding site. Ritz, D. Thioredoxin 2 is involved in the oxidative stress response in Escherichia coli. Storz, G. Transcriptional regulator of oxidative stress-inducible genes: direct activation by oxidation.

Science , — This study reports the activation of OxyR, a transcription factor that controls an oxidative stress response, through the direct oxidation of a cysteine residue, which shows that oxidation is not always detrimental.

Roles of thiol-redox pathways in bacteria. Fernandes, A. Glutaredoxins: glutathione-dependent redox enzymes with functions far beyond a simple thioredoxin backup system. Vlamis-Gardikas, A. The multiple functions of the thiol-based electron flow pathways of Escherichia coli : eternal concepts revisited.

Iwema, T. Structural basis for delivery of the intact [Fe2S2] cluster by monothiol glutaredoxin. Biochemistry 48 , — Newton, G.

Mycothiol biochemistry. Bacillithiol is an antioxidant thiol produced in bacilli. Delaye, L. Molecular evolution of peptide methionine sulfoxide reductases MsrA and MsrB : on the early development of a mechanism that protects against oxidative damage.

Brot, N. Enzymatic reduction of protein-bound methionine sulfoxide. Natl Acad. USA 78 , — This work reports, for the first time, the ability of an Msr enzyme to reduce a methionine sulfoxide in a protein.

Rahman, M. Cloning, sequencing, and expression of the Escherichia coli peptide methionine sulfoxide reductase gene.

Grimaud, R. Repair of oxidized proteins. Identification of a new methionine sulfoxide reductase. This study reports the identification of MsrB. Lin, Z. Free methionine- R -sulfoxide reductase from Escherichia coli reveals a new GAF domain function.

USA , — Ezraty, B. Methionine sulfoxide reduction and assimilation in Escherichia coli : new role for the biotin sulfoxide reductase BisC.

Kryukov, G. Selenoprotein R is a zinc-containing stereo-specific methionine sulfoxide reductase. USA 99 , — Sharov, V. Diastereoselective reduction of protein-bound methionine sulfoxide by methionine sulfoxide reductase. FEBS Lett. Moskovitz, J. Identification and characterization of a putative active site for peptide methionine sulfoxide reductase MsrA and its substrate stereospecificity.

Boschi-Muller, S. The enzymology and biochemistry of methionine sulfoxide reductases. coli methionine sulfoxide reductase with a truncated N terminus or C terminus, or both, retains the ability to reduce methionine sulfoxide. Kumar, R. Reaction mechanism, evolutionary analysis, and role of zinc in Drosophila methionine- R -sulfoxide reductase.

Kim, H. Different catalytic mechanisms in mammalian selenocysteine- and cysteine-containing methionine- R -sulfoxide reductases.

PLoS Biol. Russel, M. The role of thioredoxin in filamentous phage assembly. Construction, isolation, and characterization of mutant thioredoxins.

Methionine sulfoxide reductase: chemistry, substrate binding, recycling process and oxidase activity. This review describes the chemistry of Msr enzymes. Lee, T. An anaerobic bacterial MsrB model reveals catalytic mechanisms, advantages, and disadvantages provided by selenocysteine and cysteine in reduction of methionine- R -sulfoxide.

Coudevylle, N. Solution structure and backbone dynamics of the reduced form and an oxidized form of E. coli methionine sulfoxide reductase A MsrA : structural insight of the MsrA catalytic cycle. Ranaivoson, F. A structural analysis of the catalytic mechanism of methionine sulfoxide reductase A from Neisseria meningitidis.

Methionine sulfoxide reductase B displays a high level of flexibility. Lowther, W. The mirrored methionine sulfoxide reductases of Neisseria gonorrhoeae pilB. Mahawar, M. Synergistic roles of Helicobacter pylori methionine sulfoxide reductase and GroEL in repairing oxidant-damaged catalase. Benoit, S.

Alkyl hydroperoxide reductase repair by Helicobacter pylori methionine sulfoxide reductase. Khor, H. Potential role of methionine sulfoxide in the inactivation of the chaperone GroEL by hypochlorous acid HOCl and peroxynitrite ONOO-.

Abulimiti, A. Reversible methionine sulfoxidation of Mycobacterium tuberculosis small heat shock protein Hsp Levine, R.

Methionine residues as endogenous antioxidants in proteins. USA 93 , — This study proposes a theory in which methionine residues act as a shield against ROS.

Methionine sulfoxide reductases protect Ffh from oxidative damages in Escherichia coli. This study reports the identification of the SRP54 homologue in bacteria as a target of the MsrAB system through the use of both biochemical and physiological approaches. Luirink, J. An alternative protein targeting pathway in Escherichia coli : studies on the role of FtsY.

Ulbrandt, N. The E. coli signal recognition particle is required for the insertion of a subset of inner membrane proteins. Cell 88 , — Leverrier, P. Contribution of proteomics toward solving the fascinating mysteries of the biogenesis of the envelope of Escherichia coli.

Proteomics 10 , — Silhavy, T. The bacterial cell envelope. Cold Spring Harb. Depuydt, M. How proteins form disulfide bonds. Bardwell, J. Identification of a protein required for disulfide bond formation in vivo.

Cell 67 , — This study describes the identification of DsbA, a protein that catalyses the formation of disulfide bonds in the periplasm. Bader, M. Oxidative protein folding is driven by the electron transport system. Cell 98 , — Kadokura, H.

Detecting folding intermediates of a protein as it passes through the bacterial translocation channel. Cell , — Shevchik, V. Characterization of DsbC, a periplasmic protein of Erwinia chrysanthemi and Escherichia coli with disulfide isomerase activity.

Dutton, R. Bacterial species exhibit diversity in their mechanisms and capacity for protein disulfide bond formation. This study reveals that there is a bias for an even number of cysteine residues in proteins that are expressed in compartments in which the formation of disulfide bonds occurs.

As such, counting the number of cysteine residues can be used to predict whether the formation of disulfide bonds occurs in a specific cellular compartment.

A periplasmic reducing system protects single cysteine residues from oxidation. This paper reports the function of DsbG in the protection of single cysteine residues from oxidation in the periplasm.

Mainardi, J. Unexpected inhibition of peptidoglycan ld-transpeptidase from Enterococcus faecium by the β-lactam imipenem.

Denoncin, K. A new role for Escherichia coli DsbC protein in protection against oxidative stress. Reducing systems protecting the bacterial cell envelope from oxidative damage. Rietsch, A. Reduction of the periplasmic disulfide bond isomerase, DsbC, occurs by passage of electrons from cytoplasmic thioredoxin.

An in vivo pathway for disulfide bond isomerization in Escherichia coli. Katzen, F. Transmembrane electron transfer by the membrane protein DsbD occurs via a disulfide bond cascade. Williamson, J. Structure and multistate function of the transmembrane electron transporter CcdA.

Skaar, E. Olry, A. Characterization of the methionine sulfoxide reductase activities of PilB, a probable virulence factor from Neisseria meningitidis. The thioredoxin domain of Neisseria gonorrhoeae PilB can use electrons from DsbD to reduce downstream methionine sulfoxide reductases.

Saleh, M. Molecular architecture of Streptococcus pneumoniae surface thioredoxin-fold lipoproteins crucial for extracellular oxidative stress resistance and maintenance of virulence.

EMBO Mol. Gennaris, A. Repairing oxidized proteins in the bacterial envelope using respiratory chain electrons. Nature , — This study describes the identification of MsrPQ, which is a widely conserved enzymatic system that protects methionine residues from oxidation in the periplasm. Brokx, S.

Characterization of an Escherichia coli sulfite oxidase homologue reveals the role of a conserved active site cysteine in assembly and function. Biochemistry 44 , — Juillan-Binard, C. A two-component NADPH oxidase NOX -like system in bacteria is involved in the electron transfer chain to the methionine sulfoxide reductase MsrP.

Loschi, L. Structural and biochemical identification of a novel bacterial oxidoreductase. Melnyk, R. Novel mechanism for scavenging of hypochlorite involving a periplasmic methionine-rich peptide and methionine sulfoxide reductase.

mBio 6 , e—15 Characterization of Escherichia coli null mutants for glutaredoxin 2. Kosower, N. Diamide, a new reagent for the intracellular oxidation of glutathione to the disulfide.

Lin, K. Mycobacterium tuberculosis thioredoxin reductase is essential for thiol redox homeostasis but plays a minor role in antioxidant defense. PLoS Pathog. Uziel, O. Transcriptional regulation of the Staphylococcus aureus thioredoxin and thioredoxin reductase genes in response to oxygen and disulfide stress.

Marteyn, B. In response to oxidative DNA damage, cells activate complex signaling networks to promote DNA repair and survival or trigger cell death 2. However, when these mechanisms fail, genomic instability can lead to disease.

DNA damage can broadly be divided into that caused by exogenous factors and that which occurs endogenously. Examples of exogenous DNA damaging agents include UV radiation that causes covalent linkages to form between adjacent pyrimidines; ionizing radiation IR that generates base lesions and single strand breaks; and chemicals present in tobacco smoke that are converted into alkylating agents able to induce mispairing between bases.

Causes of endogenous DNA damage include replication errors such as base substitutions or single base insertions; spontaneous base deamination that results in base conversions; and oxidative stress, whereby ROS that are naturally present in cells damage DNA via several different mechanisms 1.

Under normal conditions, ROS are essential to cell growth and survival. For example, by interacting with critical signaling molecules, ROS drive processes including proliferation, apoptosis, and iron homeostasis, while their release from macrophages and neutrophils represents an important defense mechanism against invading pathogens 3,4.

Oxidative DNA damage has been linked to a broad range of diseases and is widely recognized for its contributory role in the initiation and progression of various types of cancer 5,6.

Repair of oxidative DNA damage: mechanisms and functions This study Rspair that there is a bias for Oxidatve even number of cysteine residues in Natural detox for reducing fatigue Oxidative damage repair are expressed Pomegranate syrup recipes compartments in which Oxidative damage repair formation damagr disulfide bonds occurs. Irwin, W. They further showed a similar change in chromatin state triggered by DDB2 at sites of UV damage. Error bars ±s. Moreover, the synthesis of collagen I and III is increased in hearts of experimental diabetic rats, a condition that was countered by antioxidant treatment Guo et al.
Oxidative damage repair

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