title: Killing of chromium-damaged cells by mismatch repair and its relevance to carcinogenesis.
abstract: Hexavalent chromium compounds are widespread environmental contaminants that are well recognized as human carcinogens and potent respiratory toxicants. Intracellular metabolism of chromium(VI) leads to the production of numerous chromium-DNA adducts that are primarily formed at the phosphate groups. The mechanism of toxicity of these DNA modifications in human cells has been uncertain for a long time because chromium and other phosphate-based adducts did not block DNA replication with purified polymerases. Our recent studies identified mismatch repair proteins as activators of toxic responses to chromium-DNA damage, which resolved an apparent discrepancy in genotoxic activity of chromium adducts in cells and in vitro. The discovered mechanism of toxicity provided the basis for a novel model of chromium carcinogenesis based on the selection of resistant clones that lack mismatch repair and progress to cancer due to high levels of spontaneous mutagenesis.
authors.affiliation: Brown University, Center for Genomics and Proteomics, Department of Pathology and Laboratory Medicine, Providence, Rhode Island 02912, USA. anatoly_zhitkovich@brown.edu
authors.forename: Anatoly
authors.initials: A
authors.lastname: Zhitkovich
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Peterson-Roth
authors.forename: Mindy
authors.initials: M
authors.lastname: Reynolds
mesh_terms: D020137:Base Pair Mismatch; D045744:Cell Line, Tumor; D002857:Chromium / Q000633:toxicity*; D018736:DNA Adducts; D004249:DNA Damage; D004260:DNA Repair; D004261:DNA Replication; D016195:G2 Phase; D006801:Humans; D066298:In Vitro Techniques; D018895:Microsatellite Repeats; D016296:Mutagenesis; D009154:Mutation; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology; D010710:Phosphates / Q000737:chemistry; D010957:Plasmids / Q000378:metabolism
chemical_list: D018736:DNA Adducts; D010710:Phosphates; D002857:Chromium