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1.
Dizdaroglu M 《Mutation research》2005,591(1-2):45-59
Oxidative damage to DNA caused by free radicals and other oxidants generate base and sugar damage, strand breaks, clustered sites, tandem lesions and DNA-protein cross-links. Oxidative DNA damage is mainly repaired by base-excision repair in living cells with the involvement of DNA glycosylases in the first step and other enzymes in subsequent steps. DNA glycosylases remove modified bases from DNA, generating an apurinic/apyrimidinic (AP) site. Some of these enzymes that remove oxidatively modified DNA bases also possess AP-lyase activity to cleave DNA at AP sites. DNA glycosylases possess varying substrate specificities, and some of them exhibit cross-activity for removal of both pyrimidine- and purine-derived lesions. Most studies on substrate specificities and excision kinetics of DNA glycosylases were performed using oligonucleotides with a single modified base incorporated at a specific position. Other studies used high-molecular weight DNA containing multiple pyrimidine- and purine-derived lesions. In this case, substrate specificities and excision kinetics were found to be different from those observed with oligonucleotides. This paper reviews substrate specificities and excision kinetics of DNA glycosylases for removal of pyrimidine- and purine-derived lesions in high-molecular weight DNA. 相似文献
2.
Korolev BG 《Genetika》2005,41(6):725-735
The review considers the role of base excision repair in maintaining the constancy of genetic information in the cell. The genetic control and biochemical mechanism are described for the first stage of base excision repair, which is catalyzed by specific enzymes, DNA glycosylases. 相似文献
3.
Mitochondrial targeting of human DNA glycosylases for repair of oxidative DNA damage. 总被引:15,自引:6,他引:9
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Oxidative damage to mitochondrial DNA has been implicated in human degenerative diseases and aging. Although removal of oxidative lesions from mitochondrial DNA occurs, the responsible DNA repair enzymes are poorly understood. By expressing the epitope-tagged proteins in COS-7 cells, we examined subcellular localizations of gene products of human DNA glycosylases: hOGG1, hMYH and hNTH1. A gene encoding for hOGG1 which excises 7,8-dihydro-8-oxoguanine (8-oxoG) from DNA generates four isoforms by alternative splicing (types 1a, 1b, 1c and 2). Three tagged isoforms (types 1b, 1c and 2) were localized in the mitochondria. Type 1a protein, which exclusively contains a putative nuclear localization signal, was sorted to the nucleus and lesser amount to the mitochondria. hMYH, a human homolog gene product of Escherichia coli mutY was mainly transported into the mitochondria. hNTH1 protein excising several pyrimidine lesions was transported into both the nucleus and mitochondria. In contrast to the three DNA glycosylases, translocation of the human major AP endonuclease (hAPE) into the mitochondria was hardly observed in COS-7 cells. These results suggest that the previously observed removal of oxidative base lesions in mitochondrial DNA is initiated by the above DNA glycosylases. 相似文献
4.
Protective action of melatonin against oxidative DNA damage: chemical inactivation versus base-excision repair 总被引:2,自引:0,他引:2
Sliwinski T Rozej W Morawiec-Bajda A Morawiec Z Reiter R Blasiak J 《Mutation research》2007,634(1-2):220-227
Melatonin is a hormone-like substance that has a variety of beneficial properties as regulator of the circadian rhythm and as anti-inflammatory and anti-cancer agent. The latter activity can be linked with the ability of melatonin to protect DNA against oxidative damage. It may exert such action either by scavenging reactive oxygen species or their primary sources, or by stimulating the repair of oxidative damage in DNA. Since such type of DNA damage is reflected in oxidative base modifications that are primarily repaired by base-excision repair (BER), we tried to investigate in the present work whether melatonin could influence this DNA-repair system. We also investigated the ability of melatonin to inactivate hydrogen peroxide, a potent source of reactive oxygen species. Melatonin at 50 microM and its direct metabolite N(1)-acetyl-N(2)-formyl-5-methoxykynuramine reduced DNA damage induced by hydrogen peroxide at approximately the same ratio. Melatonin stimulated the repair of DNA damage induced by hydrogen peroxide, as assessed by the alkaline comet assay. However, melatonin at 50 microM had no impact on the activity in vitro of three glycosylases playing a pivotal role in BER: Endo III, Fpg and ANPG 80. On the other hand, melatonin chemically inactivated hydrogen peroxide, reducing its potential to damage DNA. And finally, melatonin did not influence the repair of an a-basic (AP) site by cellular extracts, as was evaluated by a functional BER assay in vitro. In conclusion, melatonin can have a protective effect against oxidative DNA damage by chemical inactivation of a DNA-damaging agent as well as by stimulating DNA repair, but key factors in BER, viz. glycosylases and AP-endonucleases, do not seem to be affected by melatonin. Further study with other components of the BER machinery and studies aimed at other DNA-repair systems are needed to clarify the mechanism underlying the stimulation of DNA repair by melatonin. 相似文献
5.
D. O. Zharkov 《Molecular Biology》2007,41(5):702-716
DNA glycosylases play a key role in DNA repair, which maintains the integrity of the cell genome. The structures of many DNA glycosylases have been solved to date. The review considers these structures and the dynamics of DNA glycosylase interactions with DNA. The available data suggest that lesion recognition by DNA glycosylases is a highly dynamic process that is accompanied by multiple conformational changes in the enzyme and DNA substrate. 相似文献
6.
Zharkov DO 《Molekuliarnaia biologiia》2007,41(5):772-786
DNA glycosylases are key enzymes participating in the process of DNA repair, which maintains the integrity of the cellular genome. Currently, structures for many of these enzymes have been solved. This review is devoted to the analysis of these structures and the dynamics of the interactions of DNA glycosylases with DNA. The available data suggest that lesion recognition by DNA glycosylases is a highly dynamic process accompanied with multiple conformational changes in the enzyme and the DNA substrate molecules. 相似文献
7.
Sugasawa K 《Biochemistry. Biokhimii?a》2011,76(1):16-23
The nucleotide excision repair (NER) subpathway operating throughout the mammalian genome is a versatile DNA repair system
that can remove a wide variety of helix-distorting base lesions. This system contributes to prevention of blockage of DNA
replication by the lesions, thereby suppressing mutagenesis and carcinogenesis. Therefore, it is of fundamental significance
to understand how the huge genome can be surveyed for occurrence of a small number of lesions. Recent studies have revealed
that this difficult task seems to be accomplished through sequential actions of multiple DNA damage recognition factors, including
UV-DDB, XPC, and TFIIH. Notably, these factors adopt completely different strategies to recognize DNA damage. XPC detects
disruption and/or destabilization of the base pairing, which ensures a broad spectrum of substrate specificity for global
genome NER. In contrast, UV-DDB directly recognizes particular types of lesions, such as UV-induced photoproducts, thereby
vitally recruiting XPC as well as further extending the substrate specificity. After DNA binding by XPC, moreover, the helicase
activity associated with TFIIH scans a DNA strand to make a final search for the presence of aberrant chemical modifications
of DNA. The combination of these different strategies makes a crucial contribution to simultaneously achieving efficiency,
accuracy, and versatility of the entire repair system. 相似文献
8.
Pascucci B D'Errico M Parlanti E Giovannini S Dogliotti E 《Biochemistry. Biokhimii?a》2011,76(1):4-15
DNA repair is a crucial factor in maintaining a low steady-state level of oxidative DNA damage. Base excision repair (BER)
has an important role in preventing the deleterious effects of oxidative DNA damage, but recent evidence points to the involvement
of several repair pathways in this process. Oxidative damage may arise from endogenous and exogenous sources and may target
nuclear and mitochondrial DNA as well as RNA and proteins. The importance of preventing mutations associated with oxidative
damage is shown by a direct association between defects in BER (i.e. MYH DNA glycosylase) and colorectal cancer, but it is
becoming increasingly evident that damage by highly reactive oxygen species plays also central roles in aging and neurodegeneration.
Mutations in genes of the nucleotide excision repair (NER) pathway are associated with diseases, such as xeroderma pigmentosum
and Cockayne syndrome, that involve increased skin cancer risk and/or developmental and neurological symptoms. In this review
we will provide an updating of the current evidence on the involvement of NER factors in the control of oxidative DNA damage
and will attempt to address the issue of whether this unexpected role may unlock the difficult puzzle of the pathogenesis
of these syndromes. 相似文献
9.
Klungland A Höss M Gunz D Constantinou A Clarkson SG Doetsch PW Bolton PH Wood RD Lindahl T 《Molecular cell》1999,3(1):33-42
Oxidized pyrimidines in DNA are removed by a distinct base excision repair pathway initiated by the DNA glycosylase--AP lyase hNth1 in human cells. We have reconstituted this single-residue replacement pathway with recombinant proteins, including the AP endonuclease HAP1/APE, DNA polymerase beta, and DNA ligase III-XRCC1 heterodimer. With these proteins, the nucleotide excision repair enzyme XPG serves as a cofactor for the efficient function of hNth1. XPG protein promotes binding of hNth1 to damaged DNA. The stimulation of hNth1 activity is retained in XPG catalytic site mutants inactive in nucleotide excision repair. The data support the model that development of Cockayne syndrome in XP-G patients is related to inefficient excision of endogenous oxidative DNA damage. 相似文献
10.
Recent aspects of oxidative DNA damage: guanine lesions,measurement and substrate specificity of DNA repair glycosylases 总被引:2,自引:0,他引:2
Cadet J Bellon S Berger M Bourdat AG Douki T Duarte V Frelon S Gasparutto D Muller E Ravanat JL Sauvaigo S 《Biological chemistry》2002,383(6):933-943
This review discusses recent aspects of oxidation reactions of DNA and model compounds involving mostly OH radicals, one-electron transfer process and singlet oxygen (1O2). Emphasis is placed on the formation of double DNA lesions involving a purine base on one hand and either a pyrimidine base or a 2-deoxyribose moiety on the other hand. Structural and mechanistic information is also provided on secondary oxidation reactions of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodGuo), a major DNA marker of oxidative stress. Another major topic which is addressed here deals with recent developments in the measurement of oxidative base damage to cellular DNA. This has been mostly achieved using the accurate and highly specific HPLC method coupled with the tandem mass spectrometry detection technique. Interestingly, optimized conditions of DNA extraction and subsequent work-up allow the accurate measurement of 11 modified nucleosides and bases within cellular DNA upon exposure to oxidizing agents, including UVA and ionizing radiations. In addition, the modified comet assay, which involves the use of bacterial DNA N-glycosylases to reveal two main classes of oxidative base damage, is applicable to isolated cells and is particularly suitable when only small amounts of biological material are available. Finally, recently available data on the substrate specificity of DNA repair enzymes belonging to the base excision pathways are briefly reviewed. 相似文献
11.
12.
Vertebrate POLQ and POLbeta cooperate in base excision repair of oxidative DNA damage 总被引:1,自引:0,他引:1
Yoshimura M Kohzaki M Nakamura J Asagoshi K Sonoda E Hou E Prasad R Wilson SH Tano K Yasui A Lan L Seki M Wood RD Arakawa H Buerstedde JM Hochegger H Okada T Hiraoka M Takeda S 《Molecular cell》2006,24(1):115-125
Base excision repair (BER) plays an essential role in protecting cells from mutagenic base damage caused by oxidative stress, hydrolysis, and environmental factors. POLQ is a DNA polymerase, which appears to be involved in translesion DNA synthesis (TLS) past base damage. We disrupted POLQ, and its homologs HEL308 and POLN in chicken DT40 cells, and also created polq/hel308 and polq/poln double mutants. We found that POLQ-deficient mutants exhibit hypersensitivity to oxidative base damage induced by H(2)O(2), but not to UV or cisplatin. Surprisingly, this phenotype was synergistically increased by concomitant deletion of the major BER polymerase, POLbeta. Moreover, extracts from a polq null mutant cell line show reduced BER activity, and POLQ, like POLbeta, accumulated rapidly at sites of base damage. Accordingly, POLQ and POLbeta share an overlapping function in the repair of oxidative base damage. Taken together, these results suggest a role for vertebrate POLQ in BER. 相似文献
13.
While a role for DNA glycosylase activity in base excision repair (BER) is well understood, there is mounting evidence to implicate cooperation of DNA glycosylases with components of repair pathways other than BER. The mechanisms by which DNA glycosylases interact with non-BER pathways are, in many cases, poorly understood. However, accumulating evidence indicates that crosstalk is common and may be as important in signaling repair as the canonical pathways themselves. 相似文献
14.
DNA glycosylases are enzymes that initiate base excision repair, which removes damaged bases from cell DNA. Recent data demonstrate that some genetic variants of two human DNA glycosylases, MUTYH and OGG1, are associated with an increased risk of cancer. In addition, various DNA glycosylases are involved in protection from some neurodegenerative diseases, immune disorders, and virus infections. On the other hand, DNA glycosylases of pathogenic microorganisms help them to evade the host defense mechanisms. Thus, DNA glycosylases are considered to be both potential therapeutic agents and drug targets. 相似文献
15.
Product-assisted catalysis in base-excision DNA repair 总被引:7,自引:0,他引:7
Most spontaneous damage to bases in DNA is corrected through the action of the base-excision DNA repair pathway. Base excision repair is initiated by DNA glycosylases, lesion-specific enzymes that intercept aberrant bases in DNA and catalyze their excision. How such proteins accomplish the feat of catalyzing no fewer than five sequential reaction steps using a single active site has been unknown. To help answer this, we report the structure of a trapped catalytic intermediate in DNA repair by human 8-oxoguanine DNA glycosylase. This structure and supporting biochemical results reveal that the enzyme sequesters the excised lesion base and exploits it as a cofactor to participate in catalysis. To our knowledge, the present example represents the first documented case of product-assisted catalysis in an enzyme-catalyzed reaction. 相似文献
16.
Overlapping specificities of base excision repair, nucleotide excision repair, recombination, and translesion synthesis pathways for DNA base damage in Saccharomyces cerevisiae
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Swanson RL Morey NJ Doetsch PW Jinks-Robertson S 《Molecular and cellular biology》1999,19(4):2929-2935
The removal of oxidative damage from Saccharomyces cerevisiae DNA is thought to be conducted primarily through the base excision repair pathway. The Escherichia coli endonuclease III homologs Ntg1p and Ntg2p are S. cerevisiae N-glycosylase-associated apurinic/apyrimidinic (AP) lyases that recognize a wide variety of damaged pyrimidines (H. J. You, R. L. Swanson, and P. W. Doetsch, Biochemistry 37:6033-6040, 1998). The biological relevance of the N-glycosylase-associated AP lyase activity in the repair of abasic sites is not well understood, and the majority of AP sites in vivo are thought to be processed by Apn1p, the major AP endonuclease in yeast. We have found that yeast cells simultaneously lacking Ntg1p, Ntg2p, and Apn1p are hyperrecombinogenic (hyper-rec) and exhibit a mutator phenotype but are not sensitive to the oxidizing agents H2O2 and menadione. The additional disruption of the RAD52 gene in the ntg1 ntg2 apn1 triple mutant confers a high degree of sensitivity to these agents. The hyper-rec and mutator phenotypes of the ntg1 ntg2 apn1 triple mutant are further enhanced by the elimination of the nucleotide excision repair pathway. In addition, removal of either the lesion bypass (Rev3p-dependent) or recombination (Rad52p-dependent) pathway specifically enhances the hyper-rec or mutator phenotype, respectively. These data suggest that multiple pathways with overlapping specificities are involved in the removal of, or tolerance to, spontaneous DNA damage in S. cerevisiae. In addition, the fact that these responses to induced and spontaneous damage depend upon the simultaneous loss of Ntg1p, Ntg2p, and Apn1p suggests a physiological role for the AP lyase activity of Ntg1p and Ntg2p in vivo. 相似文献
17.
Plants contain the genes for both formamidopyrimidine-DNA glycosylase (FPG) and oxoguanine glycosylase (OGG). These enzymes play analogous roles in the base excision repair pathways of bacteria (FPG) and archaea, yeast, and mammals (OGG). Why have plants retained both genes? We tested one hypothesis by comparing the specificities of Arabidopsis FPG and OGG purified from Escherichia coli expression clones. Using depurinated DNA as substrate, the specific activity of Arabidopsis FPG was higher than that of Arabidopsis OGG. Using DNA oxidized by treatment with light in the presence of methylene blue, the specific activities of Arabidopsis FPG and OGG were equal. Using an oligonucleotide containing one oxoguanine (paired with C) and labeled with fluorescein, the specific activity of Arabidopsis OGG was greater than that of either FPG. The results support the hypothesis that genes for the two enzymes have been retained during evolution of plants for their specialized enzyme activities. 相似文献
18.
19.
Nagorska K Silhan J Li Y Pelicic V Freemont PS Baldwin GS Tang CM 《Molecular microbiology》2012,83(5):1064-1079
Although oxidative stress is a key aspect of innate immunity, little is known about how host‐restricted pathogens successfully repair DNA damage. Base excision repair is responsible for correcting nucleobases damaged by oxidative stress, and is essential for bloodstream infection caused by the human pathogen, Neisseria meningitidis. We have characterized meningococcal base excision repair enzymes involved in the recognition and removal of damaged nucleobases, and incision of the DNA backbone. We demonstrate that the bi‐functional glycosylase/lyases Nth and MutM share several overlapping activities and functional redundancy. However, MutM and other members of the GO system, which deal with 8‐oxoG, a common lesion of oxidative damage, are not required for survival of N. meningitidis under oxidative stress. Instead, the mismatch repair pathway provides back‐up for the GO system, while the lyase activity of Nth can substitute for the meningococcal AP endonuclease, NApe. Our genetic and biochemical evidence shows that DNA repair is achieved through a robust network of enzymes that provides a flexible system of DNA repair. This network is likely to reflect successful adaptation to the human nasopharynx, and might provide a paradigm for DNA repair in other prokaryotes. 相似文献
20.
Guanyl radical species are produced in DNA by electron removal caused by ionizing radiation, photoionization, oxidation, or photosensitization. DNA guanyl radicals can be reduced by electron donation from mild reducing agents. Important biologically relevant examples are the redox active amino acids cysteine, cystine, methionine, tryptophan, and tyrosine. We have quantified the reactivity of derivatives of these amino acids with guanyl radicals located in plasmid DNA. The radicals were produced by electron removal using the single electron oxidizing agent (SCN)(2)(*)(-). Disulfides (cystine) are unreactive. Thioethers (methionine), thiols (cysteine), and phenols (tyrosine) react with rate constants in the range 10(4)-10(6), 10(5)-10(6), and 10(5)-10(6) dm(3) mol(-1) s(-1), respectively. Indoles (tryptophan) are the most reactive with rate constants of 10(7)-10(8) dm(3) mol(-1) s(-1). Selenium analogues of amino acids are over an order of magnitude more reactive than their sulfur equivalents. Increasing positive charge is associated with a ca. 10-fold increase in reactivity. The results suggest that amino acid residues located close to DNA (for example, in DNA binding proteins such as histones) might participate in the repair of oxidative DNA damage. 相似文献