Abstract 2978: Nucleotide excision repair contributes to hexavalent chromium-induced double strand breaks and chromosomal damage

Abstract

Abstract Certain hexavalent chromium (Cr(VI)) compounds are known human lung carcinogens. Cr(VI) causes several types of DNA damage including bulky adducts and crosslinks. Cr(VI)-induced tumors exhibit chromosomal instability (CIN), however, very little is known about mechanisms of these effects and the role that DNA repair plays in this process. Nucleotide excision repair (NER) is known to be involved in the repair of bulky DNA damage. Unrepaired or misrepaired lesions can lead to chromosomal aberrations (CAs). We investigated the role of NER leading to CAs using Chinese hamster ovary (CHO) parental (AA8) and NER-deficient cells (UV-5). We found that UV-5 cells displayed attenuated Cr(VI)-induced chromosome damage. In general, DNA lesions need to be converted to DNA double strand breaks (DSBs) in order to give rise to CAs. Therefore, we used the neutral Comet assay to measure the induction and repair of DSBs after Cr(VI)-induced damage. We found that both parental and NER-deficient cell lines displayed low levels of DSBs immediately after Cr(VI) treatment. Interestingly, DSB formation peaked after a 24h recovery period, and NER-deficient cells exhibited lower overall levels of DSBs than repair-proficient cells. All damage in both cell lines was repaired by 48h following Cr(VI) exposure. Taken together, our results suggest that Cr(VI)-induced DSBs are not directly formed by Cr(VI) exposure. Instead, these lesions develop as a consequence of repair of, or replication past, Cr(VI)-induced lesions. Importantly, our data suggests that NER contributes to Cr(VI)-induced genomic instability. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2978.