Role of DNA polymerase beta in the genotoxicity of arsenic.

Abstract:

Arsenic, an important hazard in the environment, is associated with human cancer and other degenerative diseases. However, the mechanisms underlying arsenic hazardous effects remain unclear. It has been reported arsenic exposure can result in increased cellular reactive oxygen species and oxidative DNA damage. This suggests DNA base excision repair (BER), the major pathway for repairing oxidative DNA damage, may be involved in combating arsenic hazardous effects. As a critical repair enzyme in BER, DNA polymerase beta (Pol β) might play an essential role in reducing arsenic toxicity. To test this hypothesis, we evaluated arsenic-induced cytotoxic and genotoxic effects under Pol β deficiency. Our results demonstrated that the viability of Pol β-deficient mouse embryonic fibroblasts was much lower than that of Pol β wild-type cells after treatment with arsenite (As(3+) ). An increased level of DNA damage and significantly delayed arsenite-induced DNA damage repair in Pol β-deficient cells indicated reduced repair of DNA lesions under Pol β deficiency. This was consistent with the increase in the frequency of micronuclei (MN), an indicator of chromosomal breakage, which was also observed in Pol β-deficient cells treated with arsenite. In contrast, cells harboring overexpressed Pol β resulted in a lower level of DNA damage and MN than Pol β wild-type cells, indicating overexpression of the enzyme can combat arsenic-induced genotoxic effects. In conclusion, our results indicate an important role for Pol β in repairing arsenite-induced DNA damage and maintaining chromosomal integrity and further suggest deficiency of BER may be involved in arsenic genotoxicity and carcinogenicity.

Polymerases:

Topics:

Nucleotide Analogs / Template Lesions, Fidelity, Health/Disease

Status:

new topics/pols set partial results complete validated

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