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In the occupational setting, exposure to certain species of hexavalent chromium (Cr(VI)) has been associated with an increased occurrence of lung cancers. Hexavalent chromium is capable of generating a wealth of lesions recognized by multiple DNA repair pathways. Removal of the majority of Cr(VI) induced DNA base damage requires DNA excision repair. Recent data from our lab and others indicates that nucleotide excision repair (NER) and base excision repair (BER) play equally important roles in the removal of Cr(VI) damage. In this study we assessed the mutagenic capabilities Cr(VI) in repair deficient yeast (rad1 (NER) and apn1(BER) ) and Chinese hamster ovary (CHO) cells. Both CHO cell lines are deficient in excision repair proteins involved primarily in NER, XPD and XPF respectively. We utilized methoxyamine (Mx), a polymerase β inhibitor, to inhibit single nucleotide BER in CHO cells. In general, yeast and CHO cells deficient in NER and BER exhibited moderate increased sensitivity to Cr(VI) clonogenic lethality. To assess the roles of NER and BER in Cr(VI) mutagenesis we studied forward mutations at the Can1 (L-canavanine resistance) and HPRT (6-thioguanine resistance) loci in yeast and mammalian cells, respectively. Cr(VI)-induced a concentration-dependant increase in mutagenesis in WT yeast and parental CHO cells. Interestingly, when excision repair was inhibited, either genetically (yeast) or pharmacologically (CHO cells), an abrogation of Cr(VI) induced mutagenesis as seen relative to repair-proficient cells. Studies using 51Cr(VI) suggested that the hypomutagenic effect of Cr(VI) in rad1 and apn1 yeast was not due to decreased Cr(VI) uptake. In general, there was not a marked difference in toxicity between the Wt and repair-deficient strains. While Cr(VI) generates pre-mutagenic DNA lesions; the results of this study strongly suggest that the excision repair gene products are required for Cr(VI) mutagenesis as confirmed genetically and pharmacologically in two separate systems . (Supported by grants ES-05304, ES-09961 to SRP).

[Proc Amer Assoc Cancer Res, Volume 47, 2006]