Base excision repair by hNTH1 and hOGG1: A two edged sword in the processing of DNA damage in γ-irradiated human cells

Yang, Ning; Chaudhry, M. Ahmad; Wallace, Susan S.

doi:10.1016/j.dnarep.2005.07.003

Cited by 112 publications

(88 citation statements)

References 61 publications

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“…It is likely that, upon encountering a damage, the WT enzymes are proceeding to catalysis because both the buffer conditions and the enzyme/substrate ratios used in the singlemolecule assay are commensurate with the multiple turnover conditions used in our ensemble assays. Moreover, under high damage conditions, we occasionally observe the double-stranded λ DNA breaking apart because substrate lesions that are closely opposed in opposite strands can be cleaved by the lyase activity of the DNA glycosylase and result in double-strand breaks (33)(34)(35)(36).…”

Section: Resultsmentioning

confidence: 97%

Two glycosylase families diffusively scan DNA using a wedge residue to probe for and identify oxidatively damaged bases

Nelson

Dunn

Kathe

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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113

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DNA glycosylases are enzymes that perform the initial steps of base excision repair, the principal repair mechanism that identifies and removes endogenous damages that occur in an organism's DNA. We characterized the motion of single molecules of three bacterial glycosylases that recognize oxidized bases, Fpg, Nei, and Nth, as they scan for damages on tightropes of λ DNA. We find that all three enzymes use a key "wedge residue" to scan for damage because mutation of this residue to an alanine results in faster diffusion. Moreover, all three enzymes bind longer and diffuse more slowly on DNA that contains the damages they recognize and remove. Using a sliding window approach to measure diffusion constants and a simple chemomechanical simulation, we demonstrate that these enzymes diffuse along DNA, pausing momentarily to interrogate random bases, and when a damaged base is recognized, they stop to evert and excise it.DNA repair | search mechanisms O xidative DNA damage is produced endogenously during normal cellular metabolism or exogenously by chemical agents and ionizing radiation (1, 2). Oxidatively induced DNA damage resulting from attack by reactive oxygen species accounts for approximately one-half of all DNA base damages (3). Some oxidative base damages, such as thymine glycol, are blocks to DNA polymerases and thus potentially lethal; however, the majority of oxidative base lesions mispair with noncognate bases and are potentially mutagenic (4). Therefore, damaged bases must be repaired to maintain the cell's genomic integrity. With substantial in vivo steady-state levels of oxidative damages, alkylation damages, and apurinic/apyrimidinic (AP) sites among the nearly six billion normal bases, how DNA repair enzymes locate these damages in the sea of undamaged bases has been the subject of much speculation.The DNA repair mechanism responsible for the removal of the majority of endogenous DNA damages is the base excision repair (BER) pathway (4-6). The critical first step in BER is carried out by a DNA glycosylase that, fueled only by thermal energy, locates a damaged base and cleaves the N-glycosyl bond, thus removing the base lesion from the sugar phosphate backbone. Glycosylases are small monomeric proteins that are found in all living organisms and can be separated into different families based on substrate specificity and structural motifs. In Escherichia coli, there are three glycosylases, Nth, Fpg, and Nei, that directly remove oxidized DNA bases, and all three have an associated lyase activity that cleaves the DNA backbone. These glycosylases are members of two structural families, the helixhairpin-helix (HhH) or Nth superfamily and the helix-two turnshelix (H2TH) or Fpg/Nei family (7-9) (Fig. 1A). Interestingly, the HhH superfamily member, endonuclease III (Nth), and Fpg/ Nei family member, endonuclease VIII (Nei), primarily catalyze the removal of oxidized pyrimidines, such as 5,6-dihydroxy-5, 6-dihydrothymine (Tg), whereas formamidopyrimidine DNA glycosylase (Fpg) primarily removes oxidized purines...

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Section: Resultsmentioning

confidence: 97%

Two glycosylase families diffusively scan DNA using a wedge residue to probe for and identify oxidatively damaged bases

Nelson

Dunn

Kathe

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

113

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“…(40) Recent studies have found that oxidative DNA damage, including 8-OHdG lesions, create DSB thorough the BER pathway in association with action of glycosylase such as OGG1. (18) Repair of DSB by the non-homologous end-joining pathway has been thought to harbor the potential risk of creating large deletions. (41,42) In addition, potassium bromate (KBrO 3 ), a rat renal carcinogen that exerts oxidative stress leading to 8-OHdG formation, induced DNA strand brakes in V79 Chinese hamster cells, (43) LOH in mouse lymphoma cells, (20) and large deletions in human cells.…”

Section: Resultsmentioning

confidence: 99%

“…(17) In addition, during base excision repair (BER) by OGG1, 8-OHdG can cause large deletion mutations associated with double-strand brakes (DSB). (18) Furthermore, recent studies using in vitro genotoxicity assays with human lymphoblastoid TK6 cells or mouse lymphoma cells demonstrated that oxidative stress involving 8-OHdG formation induced large deletions, including loss of heterozygosity (LOH) at the TK locus. (19,20) Such data imply that hepatocarcinogens with CYP-inducible potency and classified as non-genotoxic carcinogens may oxidatively damage liver DNA and consequently induce gene mutations.…”

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confidence: 99%

Oxidative DNA damage and reporter gene mutation in the livers of gpt delta rats given non‐genotoxic hepatocarcinogens with cytochrome P450‐inducible potency

et al. 2010

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Previous reports have proposed that reactive oxygen species resulting from induction of cytochrome P450 (CYP) isozymes might be involved in the modes of action of hepatocarcinogens with CYP-inducible potency. In the present study, we investigated 8-hydroxydeoxyguanosine (8-OHdG) levels, in vivo mutagenicity and glutathione S-transferase placental form (GST-P)-positive foci in the livers of gpt delta rats treated with piperonyl butoxide (PBO) or phenobarbital (PhB) for 4 and 13 weeks. Significant elevations in Cyp 1A1 and Cyp 1A2 mRNA levels after PBO treatment, and in Cyp 2B1 mRNA levels after PBO or PhB treatment, appeared together with remarkable hepatomegaly through the experimental period. Time-dependent and statistically significant increases in 8-OHdG levels were observed in the PBO treatment group along with significant increases in proliferating cell nuclear antigen (PCNA)-positive hepatocytes at 4 weeks, while no increase in 8-OHdG levels was found in PhB-treated rats. No changes in mutant frequencies of gpt and red/gam (Spi -) genes in liver DNA from PBO-or PhB-treated rats were observed at 4 or 13 weeks. A 13-week exposure to either PBO or PhB did not affect the number and area of GST-P-positive hepatocytes. CYP 1A1 and 1A2 induction may be responsible for elevated levels of 8-OHdG in PBO-treated rats. However, neither GC:TA transversions nor deletion mutations, typically regarded as 8-OHdG-related mutations, were observed in any of the treated rats. We conclude that reactive oxygen species, possibly produced through CYP catalytic pathways, likely induced genomic DNA damage but did not give rise to permanent gene mutation. (Cancer Sci 2010; 101: 2525-2530 O xidative stress induces cell proliferation due to either activation of various transcriptional genes related to the cell cycle or to site-specific toxicity. As such, oxidative stress may take part in non-genotoxic carcinogenesis.(1,2) Exposure to exogenous chemicals are able to yield oxidative stress in the body by various ways such as their oxidizing properties, (3) production of radicals through a redox cycle in their metabolism, (4) depletion of glutathione resulting from utilization for their conjugation, (5) and their cytochrome P450 (CYP)-mediated metabolizing pathways.(6) All of these mechanisms for generating oxidative stress are characterized by having site specificity. In addition, all of the above cases except oxidizing properties require in vivo metabolism to produce oxidative stress, which may be the major reason why such chemicals fail to show genotoxicity in conventional mutagenicity tests. The CYP act on a wide variety of chemicals, and CYP involvement in the production of reactive oxygen species during substrate oxidation is well documented.(7-9) However, since the amount of free radicals generated through the normal catalytic cycle is small, (10) induction of CYP might be necessary for any associated oxidative properties to play a role in carcinogenesis in vivo. Various chemicals with CYP-inducible properties demonstrate hepatocar...

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“…Indirectly, however, they might also be involved in HR; both in E. coli and in human cells it was shown that BER can lead to the formation of DSBs if two opposing damaged bases are being incised by EndoIII at the same time. Interestingly, deletion mutants of EndoIII show a reduced formation of DSBs but are more sensitive to radiation (62)(63)(64)(65)(66). Eccles et al (67) discussed that repair of opposing DNA lesions by the BER pathway is slow and delayed and might induce DNA mutation or replication breakdown; however, if the opposing DNA lesions are incised only by EndoIII and not processed by the other BER proteins, a DSB which is repaired much faster occurs (67).…”

Section: Figmentioning

confidence: 99%

DNA Processing Proteins Involved in the UV-Induced Stress Response of Sulfolobales

Wolferen

Albers

2015

J Bacteriol

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The ups operon of Sulfolobus species is highly induced upon UV stress. Previous studies showed that the pili encoded by this operon are involved in cellular aggregation, which is essential for subsequent DNA exchange between cells, resulting in homologous recombination. The presence of this pilus system increases the fitness of Sulfolobus cells under UV light-induced stress conditions, as the transfer of DNA takes place in order to repair UV-induced DNA lesions via homologous recombination. Four conserved genes (saci_1497 to saci_1500) which encode proteins with putative DNA processing functions are present downstream of the ups operon. In this study, we show that after UV treatment the cellular aggregation of strains with saci_1497, saci_1498, and saci_1500 deletions is similar to that of wild-type strains; their survival rates, however, were reduced and similar to or lower than those of the pilus deletion strains, which could not aggregate anymore. DNA recombination assays indicated that saci_1498, encoding a ParB-like protein, plays an important role in DNA transfer. Moreover, biochemical analysis showed that the endonuclease III encoded by saci_1497 nicks UV-damaged DNA. In addition, RecQ-like helicase Saci_1500 is able to unwind homologous recombination intermediates, such as Holliday junctions. Interestingly, a saci_1500 deletion mutant was more sensitive to UV light but not to the replication-stalling agents hydroxyurea and methyl methanesulfonate, suggesting that Saci_1500 functions specifically in the UV damage pathway. Together these results suggest a role of Saci_1497 to Saci_1500 in the repair or transfer of DNA that takes place after UV-induced damage to the genomic DNA of Sulfolobus acidocaldarius. IMPORTANCESulfolobales species increase their fitness after UV stress by a UV-inducible pilus system that enables high rates of DNA exchange between cells. Downstream of the pilus operon, three genes that seem to play a role in the repair or transfer of the DNA between Sulfolobus cells were identified, and their possible functions are discussed. Next to the previously described role of UV-inducible pili in the exchange of DNA, we have thereby increased our knowledge of DNA transfer at the level of DNA processing. This paper therefore contributes to the overall understanding of the DNA exchange mechanism among Sulfolobales cells. In all domains of life, DNA repair is crucial for maintenance of genome integrity upon exposure to intra-or extracellular DNAdamaging threats (1). Unlike DNA repair in bacteria, archaeal DNA repair and its regulation are still far from well understood (1, 2). Homology searches revealed that the proteins in archaeal DNA repair pathways show similarities to both bacterial and eukaryotic proteins. In addition, DNA repair proteins with unique archaeal features exist (3).Previously, it was speculated that archaea might have SOS-like responses similar to those in certain bacteria (4); however, microarray studies revealed that neither Haloarchaea (5, 6) nor Sulfolobus species (7...

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Base excision repair by hNTH1 and hOGG1: A two edged sword in the processing of DNA damage in γ-irradiated human cells

Cited by 112 publications

References 61 publications

Two glycosylase families diffusively scan DNA using a wedge residue to probe for and identify oxidatively damaged bases

Two glycosylase families diffusively scan DNA using a wedge residue to probe for and identify oxidatively damaged bases

Oxidative DNA damage and reporter gene mutation in the livers of gpt delta rats given non‐genotoxic hepatocarcinogens with cytochrome P450‐inducible potency

DNA Processing Proteins Involved in the UV-Induced Stress Response of Sulfolobales

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