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Human DNA polymerase beta polymorphism, Arg137Gln, impairs its polymerase activity and interaction with PCNA and the cellular base excision repair capacity.

ABSTRACT: DNA polymerase beta (Pol beta) is a key enzyme in DNA base excision repair, and an important factor for maintaining genome integrity and stability. More than 30% of human tumors characterized to date express DNA Pol beta variants, many of which result from a single nucleotide residue substitution. However, in most cases, their precise functional deficiency and relationship to cancer susceptibility are still unknown. In the current work, we show that a polymorphism encoding an arginine to glutamine substitution, R137Q, has lower polymerase activity. The substitution also affects the interaction between Pol beta and proliferating cell nuclear antigen (PCNA). These defects impair the DNA repair capacity of Pol beta in reconstitution assays, as well as in cellular extracts. Expression of wild-type Pol beta in pol beta(-/-) mouse embryonic fibroblast (MEF) cells restored cellular resistance to DNA damaging reagents such as methyl methanesulfonate (MMS) and N-methyl-N-nitrosourea (MNU), while expression of R137Q in pol beta(-/-) MEF cells failed to do so. These data indicate that polymorphisms in base excision repair genes may contribute to the onset and development of cancers.

SUBMITTER: Guo Z

PROVIDER: S-EPMC2691839 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundLast few years, several studies all over the world revealed the association of DNA repair genes with risk of developing different type of cancers, but were ambiguous to support the evidences in case of cervical cancer risk. These differences in earlier studies directed us to study the association of polymorphisms of BER genes (XRCC1, hOGG1, XPC) and NER genes (XPC, XPD) with cervical cancer susceptibility in the women of rural population of Maharashtra.Materials and methodsThe genetic polymorphism in BER and NER pathway genes was studied by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method using DNA isolated from intravenous blood samples of patients and normal controls. The study included 400 clinically confirmed cervical cancer patients and 400 healthy women from a tertiary care hospital (Krishna Hospital and Medical Research Centre) of south-western Maharashtra. The association of polymorphisms was confirmed by Odds ratio (OR) with 95% confidence interval.ResultsThe single nucleotide polymorphism (SNP) of BER genes including XRCC1, hOGG1 and APE1 were analyzed and the results were noted that 27466AA (OR=4.88; 95% CI: 3.61- 6.60; p<0.0001) and 28152AA (OR=2.89; 95% CI: 1.57- 5.31; p=0.0005) genotypes of XRCC1 (rs25489, rs25487) were significantly associated with cervical cancer risk. The 1245GG genotype of hOGG1 (rs1052133) (OR=45.30; 95% CI: 3.76- 7.46; p=0.001) also showed significant correlation, whereas 2197GG genotype of APE1 (rs1130409) gene showed negative association with cervical carcinogenesis (OR=0.59; 95% CI: 0.35- 0.97; p=0.005). Similarly when we studied SNPs of NER genes including XPC and XPD genes, 21151TT genotype of XPC (rs 2228000) was positively associated with cervical cancer development and 23591AA genotype of XPD (rs1799793) showed negative association (OR=0.34; 95% CI: 0.17- 0.64; p=0.001).ConclusionThe findings from this study supported that rs25489, rs25487SNPs of XRCC1, rs1052133 of hOGG1 and rs2228000 of XPC may increase cervical cancer risk, whereas rs1130409 SNP of APE1 and rs1799793 SNP of XPD gene lower the risk of cervical cancer in the studied population.

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Human DNA polymerase beta polymorphism, Arg137Gln, impairs its polymerase activity and interaction with PCNA and the cellular base excision repair capacity.

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