The base excision repair: mechanisms and its relevance for cancer susceptibility

Fortini, Paola; Pascucci, Barbara; Parlanti, Eleonora; D’Errico, Mariarosaria; Simonelli, Valeria; Dogliotti, Eugenia

doi:10.1016/j.biochi.2003.11.003

Cited by 196 publications

(148 citation statements)

References 185 publications

Supporting

Mentioning

141

Contrasting

Unclassified

Order By: Relevance

“…The risk of sporadic CRC is modified mainly (approximately 80%) by environmental and lifestyle factors that could be a source of DNA-damaging carcinogens [6]. Thus, the capacity for DNA-repair, determined by the polymorphisms in DNA-repair genes, seems to be essential in ensuring genomic (molecular and chromosomal) stability, which in turn is strongly associated with the risk of sCRC.…”

Section: Introductionmentioning

confidence: 99%

“…The base excision repair (BER) pathway is involved mainly in the removal of oxidative DNA damage induced by reactive oxygen species [5]. The 8-oxoguanine DNA glycosyslase (OGG1) gene encodes a DNA repair protein that removes 8-oxo-7,8-dihydroguanine (8-oxoG) [6]. The variant allele of the Ser326Cys polymorphism is associated with higher level of genetic instability and seems to be associated with an increased risk of lung, esophagus, prostate cancer as well as ALL (acute lymphoblastic leukemia) among children [7][8][9].…”

Section: Introductionmentioning

confidence: 99%

“…Opinion is divided as to whether there is an association between OGG1, Ser326Cys and colorectal cancer [8,10,11]. The XRCC1 gene encodes a protein that interacts with other DNA-repair proteins, such as Lig3, Polβ and PARP, creating a complex involved in short-patch BER [6]. Two polymorphisms: Arg194Trp and Arg399Gln have been widely studied in cancer epidemiology.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

The C/A polymorphism in intron 11 of the XPC gene plays a crucial role in the modulation of an individual’s susceptibility to sporadic colorectal cancer

et al. 2011

View full text Add to dashboard Cite

Abstract:Background: Epidemiological data show that colorectal cancer (CRC) is the second most frequent malignancy worldwide. The involvement of "minor impact genes" such as XME and DNA-repair genes in the etiology of sporadic cancer has been postulated by other authors.Aim: we focused on analyzing polymorphisms in DNA-repair genes in CRC. We considered the following genes involved in DNA-repair pathways: base excision repair (OGG1 Ser326Cys, XRCC1 Trp194Arg and Arg399Gln); nucleotide excision repair [XPA (-4)G/A, XPC C/A (i11) and A33512C (Lys939Gln), XPD Asp312Asn and A18911CMaterial and methods: The study group consisted of 133 patients diagnosed with sporadic CRC, while the control group was composed of 100 age-matched non-cancer volunteers. Genotyping was performed by PCR and PCR-RFLP. Fisher's exact test with a Bonferroni correction for multiple testing was used.Results: We found that: i) XPC C/A (i11) heterozygous variant is associated with increased risk of CRC [OR is 2.07 (95% CI 1.1391,3.7782) p=0.038], ii) XPD A18911C (Lys751Gln) is associated with decreased risk of CRC [OR=0.4497, (95% CI 0.2215,0,9131) p=0.031] for an individual with at least one A allele at this locus. Conclusions:1. the XPC C/A (i11) genotype is associated with an increased risk of sporadic colorectal cancer.2. the NER pathway has been highlighted in our study, as a most important in modulation of individual susceptibility to sCRC.

show abstract

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

The C/A polymorphism in intron 11 of the XPC gene plays a crucial role in the modulation of an individual’s susceptibility to sporadic colorectal cancer

et al. 2011

View full text Add to dashboard Cite

show abstract

“…The most common intermediates or forms of DNA damage include base modifications, abasic sites, and singlestrand breaks. These lesions are typically recognized and removed by the concerted effort of proteins that function in the base excision repair (BER) pathway (5). More complex lesions, such as DNA double-strand breaks, are corrected by recombinational repair responses (6).…”

Section: Introductionmentioning

confidence: 99%

A Dominant-Negative Form of the Major Human Abasic Endonuclease Enhances Cellular Sensitivity to Laboratory and Clinical DNA-Damaging Agents

McNeill

Wilson

2007

Molecular Cancer Research

109

View full text Add to dashboard Cite

Apurinic/apyrimidinic (AP) endonuclease 1 (APE1) is the primary enzyme in mammals for the repair of abasic sites in DNA, as well as a variety of 3 ¶ damages that arise upon oxidation or as products of enzymatic processing. If left unrepaired, APE1 substrates can promote mutagenic and cytotoxic outcomes. We describe herein a dominant-negative form of APE1 that lacks detectable nuclease activity and binds substrate DNA with a 13-fold higher affinity than the wild-type protein. This mutant form of APE1, termed ED, possesses two amino acid substitutions at active site residues Glu 96 (changed to Gln) and Asp 210 (changed to Asn). In vitro biochemical assays reveal that ED impedes wild-type APE1 AP site incision function, presumably by binding AP-DNA and blocking normal lesion processing. Moreover, tetracycline-regulated (tet-on) expression of ED in Chinese hamster ovary cells enhances the cytotoxic effects of the laboratory DNA-damaging agents, methyl methanesulfonate (MMS; 5.4-fold) and hydrogen peroxide (1.5-fold). This MMS-induced, ED-dependent cell killing coincides with a hyperaccumulation of AP sites, implying that excessive DNA damage is the cause of cell death. Because an objective of the study was to identify a protein reagent that could be used in targeted gene therapy protocols, the effects of ED on cellular sensitivity to a number of chemotherapeutic compounds was tested. We show herein that ED expression sensitizes Chinese hamster ovary cells to the killing effects of the alkylating agent 1,3-bis(2-chloroethyl)-1-nitrosourea (also known as carmustine) and the chain terminating nucleoside analogue dideoxycytidine (also known as zalcitabine), but not to the radiomimetic bleomycin, the nucleoside analogue B-D-arabinofuranosylcytosine (also known as cytarabine), the topoisomerase inhibitors camptothecin and etoposide, or the cross-linking agents mitomycin C and cisplatin. Transient expression of ED in the human cancer cell line NCI-H1299 enhanced cellular sensitivity to MMS, 1,3-bis(2-chloroethyl)-1-nitrosourea, and dideoxycytidine, demonstrating the potential usefulness of this strategy in the treatment of human tumors.

show abstract

“…Two sub-pathways of mammalian BER function redundantly to complete repair ( Figure 1A). In short patch BER, the Pol X family polymerase Pol β fills the 1-nt gap and removes the 5' dRP with its lyase activity [12,13]. In the long patch pathway, either Pol δ or Pol β performs displacement synthesis [14,15], yielding a 5' flap, which is cleaved by FEN-1 (Rad27 in yeast) [16].…”

Section: Introductionmentioning

confidence: 99%

Evidence that base stacking potential in annealed 3′ overhangs determines polymerase utilization in yeast nonhomologous end joining

Daley

Wilson

2008

DNA Repair

View full text Add to dashboard Cite

Nonhomologous end joining (NHEJ) directly rejoins DNA double-strand breaks (DSBs) when recombination is not possible. In Saccharomyces cerevisiae, the DNA polymerase Pol4 is required for gap filling when a short 3' overhang must prime DNA synthesis. Here, we examined further end variations to test specific hypotheses regarding Pol4 usage in NHEJ in vivo. Surprisingly, Pol4 dependence at 3' overhangs was reduced when a nonhomologous 5' flap nucleotide was present across from the gap, even though the mismatched nucleotide was resynthesized, not incorporated. In contrast, a gap with a 5' deoxyribosephosphate (dRP) was as Pol4-dependent as a gap with a 5' phosphate, demonstrating the importance of the downstream base in relaxing the Pol4 requirement. Combined with prior observations of Pol4-independent NHEJ of nicks with 5' hydroxyls, we suggest that base stacking interactions across the broken strands can stabilize a joint, allowing another polymerase to substitute for Pol4. This model predicts that a unique function of Pol4 is to actively stabilize template strands that lack stacking continuity. We also explored whether NHEJ end processing can occur via short and long patch pathways analogous to base excision repair. Results demonstrated that 5' dRPs could be removed in the absence of Pol4 lyase activity. The 5' flap endonuclease Rad27 was not required for repair in this or any situation tested, indicating that still other NHEJ 5' nucleases must exist.

show abstract

The base excision repair: mechanisms and its relevance for cancer susceptibility

Cited by 196 publications

References 185 publications

The C/A polymorphism in intron 11 of the XPC gene plays a crucial role in the modulation of an individual’s susceptibility to sporadic colorectal cancer

The C/A polymorphism in intron 11 of the XPC gene plays a crucial role in the modulation of an individual’s susceptibility to sporadic colorectal cancer

A Dominant-Negative Form of the Major Human Abasic Endonuclease Enhances Cellular Sensitivity to Laboratory and Clinical DNA-Damaging Agents

Evidence that base stacking potential in annealed 3′ overhangs determines polymerase utilization in yeast nonhomologous end joining

Contact Info

Product

Resources

About