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Carcinogenesis Advance Access published online on March 10, 2008
Carcinogenesis, doi:10.1093/carcin/bgn058
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Excision Repair is Required for Genotoxin-Induced Mutagenesis in Mammalian Cells

Bradford Brooks1,#,*, Travis J. O'Brien1,2,*, Susan Ceryak1,2, John Pierce Wise, Sr4,5,6, Sandra S. Wise4,5, John Pierce Wise, Jr4,5, Edward DeFabo3 and Steven R. Patierno1,2,3

1 Department of Pharmacology and Physiology
2 GW Cancer Institute
3 Department of Environmental and Occupational Health, The George Washington University Medical Center, 2300 I Street NW, Washington, DC 20037
4 Wise Laboratory of Environmental and Genetic Toxicology
5 Maine Center for Toxicology and Environmental Health, and
6 Department of Applied Medical Sciences, University of Southern Maine, Portland, Maine, 04104

cansrp{at}gwumc.edu

Certain hexavalent chromium [Cr(VI)] compounds are human lung carcinogens. Although much is known about Cr-induced DNA damage, very little is known about mechanisms of Cr(VI) mutagenesis and the role that DNA repair plays in this process. Our goal was to investigate the role of excision repair pathways in Cr(VI)-mediated mutagenesis in mammalian cells. Repair-proficient Chinese hamster ovary (CHO) cells (AA8), nucleotide excision repair (NER)-deficient (UV-5) and base excision repair (BER)-inhibited cells were treated with Cr(VI) and monitored for forward mutation frequency at the HPRT locus. BER was inhibited using methoxyamine hydrochloride (Mx) which binds to AP sites generated during BER. Notably, we found that both NER-deficient (UV-5, UV-41) and BER-inhibited (AA8 + Mx) cells displayed attenuated Cr(VI) mutagenesis. To determine whether this was unique to Cr(VI), we included the alkylating agent, methylmethane sulfonate (MMS) and ultraviolet radiation (260 nm) in our studies. Similar to Cr(VI), UV-5 cells exhibited a marked attenuation of MMS mutagenesis, but were hypermutagenic following UV exposure. Moreover, UV-5 cells expressing human XPD displayed similar sensitivity to Cr(VI) and MMS induced mutagenesis as AA8 controls indicating that the genetic loss of NER was responsible for attenuated mutagenesis. Interestingly, Cr(VI)-induced clastogenesis was also attenuated in NER-deficient and BER-inhibited cells. Taken together, our results suggest that NER and BER are required for Cr(VI) and MMS-induced genomic instability. We postulate that, in the absence of excision repair, DNA damage is channeled into an error-free system of DNA repair or damage tolerance.

Key Words: CHO • Cr(VI) • Methoxyamine • nucleotide excision repair • base excision repair • mutagenesis

* These authors contributed equally to this work

# This work was conducted in partial fulfillment of the requirements for the Ph.D. degree in Molecular and Cellular Oncology, Columbian Graduate School of Arts and Sciences, The George Washington University

Received November 26, 2007; revised February 6, 2008; accepted February 12, 2008.


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