Effects of arsenic on DNA repair and cell cell checkpoints: Involvement in arsenic co-mutagenesis and co-carcinogenesis

Arsenic is a well-documented human carcinogen associated with a variety of cancers, though the mechanism of action is unknown. Arsenic is also currently being used to treat some cancers. The paradoxical action of arsenic as both a carcinogen and a chemotherapeutic agent drug may be due to its ability to synergize with other genotoxic agents. Such synergy has been hypothesized to involve effects on DNA repair and/or cell cycle checkpoints.; Although arsenic is a carcinogen, attempts to prove arsenic carcinogenesis in animals models have been unsuccessful, leading to the hypothesis that arsenic might act as a co-carcinogen instead of a carcinogen itself. Consistent with a co-carcinogenic model, arsenic by itself does not induce mutations in most bacterial or mammalian systems tested, instead it potentiates the mutagenicity of other agents such as ultraviolet (UV), Benzo(a)Pyrene and N-methyl-N-nitrosourea (NMU). While the mechanism of this co-mutagenicity remains unknown, a possible explanation is that arsenic inhibits DNA repair, specifically nucleotide excision repair (NER). To test this hypothesis, we have completed multiple experiments using low concentrations of arsenite in cultured human cells. Our results showed that at a concentration of 2.5 muM, arsenic induced insertion/deletion mutations in a mutagenesis model using a shuttle vector pZ189, and synergistically enhanced UV mutagenicity in the same model, while it did not alter the UV mutation spectra. In cell culture, arsenic did not increase the generation of UV-induced thymine dimers, but did inhibit the removal of the dimers. In addition, arsenic at 1--5 muM enhanced and prolonged RPA-p34 hyper-phosphorylation induced by UV irradiation, suggesting the persistence of DNA damage. Arsenic did not alter expression of several critical NER proteins or inhibit the incision of UV-induced photoproducts in an in vitro incision assay. Together, these results suggest that arsenic inhibits NER, and perhaps only one subtype of NER, transcription-coupled repair. Further work though is required to identify the mechanism of this inhibition, and the exact process(es) affected.; Cell cycle checkpoint pathways are surveillance mechanisms that help maintain genomic integrity. The absence of normal checkpoint functions can lead to premature progression through the cell cycle, insufficient time for DNA repair or failure to eliminate damaged cells. Any of these events will lead to an increased risk of genomic instability and its associated risk of malignant transformation. Current evidence suggested that arsenic may suppress cell cycle checkpoints, leading to genomic instability under insults of DNA-damaging agents. (Abstract shortened by UMI.)...