Carcinogenic activity of hexavalent chromium (Cr) compounds is firmly established by experimental and epidemiological studies. Human exposure to Cr(VI) is found in several dozen occupations and detected in populations residing in the vicinity of Cr-emitting industrial sources and Cr disposal sites. Cr(Vl) is a major air pollutant and a Superfund contaminant. The major form of DNA damage in Cr(VI)-exposed cells is abundant Cr-DNA adducts generated in the reactions of stable Cr(III) form with DNA phosphates. We have found that several Cr-DNA adducts were mutagenic during replication in human cells. Ternary DNA adducts containing bulky ligands, such as glutathione or ascorbate, induced the strongest mutagenic responses. We also determined that Cr(III)-dependent reactions were responsible for the formation of mutagenic DNA damage during reductive activation of Cr(VI) by its major biological reducers, cysteine and ascorbate. Additional data have shown that biological consequences of the formation of Cr(III)-DNA adducts are strongly influenced by the status of DNA mismatch repair system. We propose to elucidate the mechanisms of mismatch repair-dependent induction of stress signaling and formation of genetic alterations in Cr(VI)- exposed cells. Experiments will be performed to identify specific Cr-DNA adducts that are recognized by DNA mismatch repair and activate genotoxic responses. The results of this work should provide a greater understanding of molecular basis of Cr(VI) carcinogenesis, the importance of individual Cr-DNA adducts and uncover new functions of mismatch repair in recognition of DNA backbone modifications. Identification of the most potent genotoxic Cr-DNA adducts and critical pathways controlling cellular responses to Cr(VI) can be used in the development of useful biomarkers of exposure and individual susceptibility to adverse health effects.
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