Base excision repair of ionizing radiation-induced DNA damage in G1 and G2 cell cycle phases

Chaudhry, M. Ahmad

doi:10.1186/1475-2867-7-15

Cited by 48 publications

(39 citation statements)

References 40 publications

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“…We also note that recent studies have demonstrated a cell cycle or proliferation state dependence in the activity of some DNA repair proteins, including several in the BER pathway (47,48). However, our previous studies have established that although BRCA1 can contribute to stress-activated cell cycle checkpoints, neither overexpression (WTBRCA1) nor underexpression (BRCA1-siRNA) of BRCA1 significantly altered the in vitro growth rate or cell cycle distribution of established cancer cell lines grown under standard cell culture conditions (Dulbecco's modified Eagle's medium plus 5-10% fetal calf serum) (22,27,50).…”

Section: Discussionmentioning

confidence: 77%

Transcriptional Regulation of the Base Excision Repair Pathway by BRCA1

Saha

Rih

Roy

et al. 2010

Journal of Biological Chemistry

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Inactivation of the breast cancer susceptibility gene BRCA1 plays a significant role in the development of a subset of breast cancers, although the major tumor suppressor function of this gene remains unclear. Previously, we showed that BRCA1 induces antioxidant-response gene expression and protects cells against oxidative stress. We now report that BRCA1 stimulates the base excision repair pathway, a major mechanism for the repair of oxidized DNA, by stimulating the activity of key base excision repair (BER) enzymes, including 8-oxoguanine DNA glycosylase (OGG1), the DNA glycosylase NTH1, and the apurinic endonuclease redox factor 1/apurinic endonuclease 1 (REF1/APE1), in human breast carcinoma cells. The increase in BER enzyme activity appears to be due, primarily, to an increase in enzyme expression. The ability of BRCA1 to stimulate the expression of the three BER enzymes and to enhance NTH1 promoter activity was dependent upon the octamerbinding transcription factor OCT1. Finally, we found that OGG1, NTH1, and REF1/APE1 each contribute to the BRCA1 protection against oxidative stress due to hydrogen peroxide and that hydrogen peroxide stimulates the expression of BRCA1 and the three BER enzymes. These findings identify a novel mechanism through which BRCA1 may regulate the repair of oxidative DNA damage. The base excision repair (BER)2 pathway is an evolutionarily conserved mechanism for repair of several types of DNA lesions, including oxidative lesions, alkylation, and incorporation of inappropriate bases (1). The primary source of these lesions is reactive oxygen species, whether generated endogenously or due to genotoxic agents. The BER pathway functions to maintain genomic integrity via a high fidelity repair process and is thus anti-mutagenic and anti-carcinogenic (2). This pathway usually has four or five enzymatic steps, involving a DNA glycosylase (e.g. OGG1 or NTH1), an AP endonuclease (REF1/APE1), a DNA polymerase (e.g. polymerase B and D), and a DNA ligase (ligase I or III) (3).DNA glycosylases recognize specific subsets of damaged bases, excise the damaged base, and may also incise at the site of the excised base due to an intrinsic lyase activity (e.g. OGG1 and NTH1). REF1/APE1 (the only mammalian AP endonuclease) then cleaves the abasic site to form a 3Ј-OH end and a 5Ј-deoxyribose phosphate end. The remaining steps may utilize a "long patch" or "short patch" pathway involving repair DNA synthesis and strand ligation by different sets of proteins. The preferred substrates for the DNA glycosylases OGG1 (8-oxoguanine glycosylase 1) and NTH1 (homolog of Escherichia coli endonuclease III) are 8-oxoguanine and thymine glycol (TG) lesions, respectively. REF1/APE1 (redox factor 1/apurinic endonuclease 1) is a multifunctional enzyme with AP endonuclease activity and 3Ј,5Ј-exonuclease, 3Ј-diesterase, and 3Ј-phosphatase activities. REF1/APE1 also has transcriptional regulatory activity independently of its function in BER (4, 5). Finally, the XRCC1 protein (x-ray repair, cross-complementing defective, ...

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Section: Discussionmentioning

confidence: 77%

Transcriptional Regulation of the Base Excision Repair Pathway by BRCA1

Saha

Rih

Roy

et al. 2010

Journal of Biological Chemistry

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“…Our measurements in these tissues will disproportionately reflect the activities of highly differ- Narciso et al (2007) demonstrated that a significant reduction in BER capacity occurs during differentiation of actively mitotic skeletal muscle progenitors (myoblasts) to post-mitotic myotubes (myofiber-like). Other authors have shown that BER enzyme activities are upregulated at specific times during the cell cycle (Chaudhry 2007) and are generally elevated in tissues containing higher proportions of actively mitotic cells (see Karahalil et al 2002). Perhaps the expected correlations of DNA repair activities with MLSP manifest in actively mitotic cells.…”

Section: Discussionmentioning

confidence: 96%

Activities of DNA base excision repair enzymes in liver and brain correlate with body mass, but not lifespan

Page

Stuart

2011

AGE

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Accumulation of DNA lesions compromises replication and transcription and is thus toxic to cells. DNA repair deficiencies are generally associated with cellular replicative senescence and premature aging syndromes, suggesting that efficient DNA repair is required for normal longevity. It follows that the evolution of increasing lifespan amongst animal species should be associated with enhanced DNA repair capacities. Although UV damage repair has been shown to correlate positively with mammalian species lifespan, we lack similar insight into many other DNA repair pathways, including base excision repair (BER). DNA is continuously exposed to reactive oxygen species produced during aerobic metabolism, resulting in the occurrence of oxidative damage within DNA. Shortpatch BER plays an important role in repairing the resultant oxidative lesions. We therefore tested whether an enhancement of BER enzyme activities has occurred concomitantly with the evolution of increased maximum lifespan (MLSP). We collected brain and liver tissue from 15 vertebrate endotherm species ranging in MLSP over an order of magnitude. We measured apurinic/ apyrimidinic (AP) endonuclease activity, as well as the rates of nucleotide incorporation into an oligonucleotide containing a single nucleotide gap (catalyzed by BER polymerase β) and subsequent ligation of the oligonucleotide. None of these activities correlated positively with species MLSP. Rather, nucleotide incorporation and oligonucleotide ligation activities appeared to be primarily (and negatively) correlated with species body mass.

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“…Treatment options for gliomas include surgical resection followed by chemotherapy with temozolomide (TMZ) or radiation, both of which generate lesions repaired by the BER pathway (Evans et al, 2000;Chaudhry, 2007;Stupp et al, 2007). These treatments rarely result in complete remission and are often accompanied by adverse toxic effects in longer surviving patients (Stupp et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

Novel Small-Molecule Inhibitor of Apurinic/Apyrimidinic Endonuclease 1 Blocks Proliferation and Reduces Viability of Glioblastoma Cells

Bapat¹,

Glass²,

Luo³

et al. 2010

J Pharmacol Exp Ther

100

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Apurinic/apyrimidinic (AP) endonuclease 1 (Ape1) is an essential DNA repair protein that plays a critical role in repair of AP sites via base excision repair. Ape1 has received attention as a druggable oncotherapeutic target, especially for treating intractable cancers such as glioblastoma. The goal of this study was to identify small-molecule inhibitors of Ape1 AP endonuclease. For this purpose, a fluorescence-based high-throughput assay was used to screen a library of 60,000 small-molecule compounds for ability to inhibit Ape1 AP endonuclease activity. Four compounds with IC 50 values less than 10 M were identified, validated, and characterized. One of the most promising compounds, designated Ape1 repair inhibitor 03 [2,4,9-trimeth-]-naphthyridin-5-amine; AR03), inhibited cleavage of AP sites in vivo in SF767 glioblastoma cells and in vitro in whole cell extracts and inhibited purified human Ape1 in vitro. AR03 has low affinity for double-stranded DNA and weakly inhibits the Escherichia coli endonuclease IV, requiring a 20-fold higher concentration than for inhibition of Ape1. AR03 also potentiates the cytotoxicity of methyl methanesulfonate and temozolomide in SF767 cells. AR03 is chemically distinct from the previously reported small-molecule inhibitors of Ape1. AR03 is a novel small-molecule inhibitor of Ape1, which may have potential as an oncotherapeutic drug for treating glioblastoma and other cancers.

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Base excision repair of ionizing radiation-induced DNA damage in G1 and G2 cell cycle phases

Cited by 48 publications

References 40 publications

Transcriptional Regulation of the Base Excision Repair Pathway by BRCA1

Transcriptional Regulation of the Base Excision Repair Pathway by BRCA1

Activities of DNA base excision repair enzymes in liver and brain correlate with body mass, but not lifespan

Novel Small-Molecule Inhibitor of Apurinic/Apyrimidinic Endonuclease 1 Blocks Proliferation and Reduces Viability of Glioblastoma Cells

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