Mutation Research 626 (2007) 120–127 Role of the Fancg gene in protecting cells from particulate chromate-induced chromosome instability Laura C. Savery a,b , Eliza Grlickova-Duzevik a,b , Sandra S. Wise a,b , W. Douglas Thompson a,c , John M. Hinz d , Larry H. Thompson d , John Pierce Wise Sr. a,b,∗ a Wise Laboratory of Environmental and Genetic Toxicology, University of Southern Maine, 96 Falmouth Street, P.O. Box 9300, Portland, ME 04104-9300, USA b Maine Center for Toxicology and Environmental Health, University of Southern Maine, 96 Falmouth Street, P.O. Box 9300, Portland, ME 04104-9300, USA c Department of Applied Medical Science, University of Southern Maine, 96 Falmouth Street, P.O. Box 9300, Portland, ME 04104-9300, USA d Biosciences Directorate, Lawrence Livermore National Laboratory, Livermore, CA 94551, USA Received 10 July 2006; received in revised form 14 September 2006; accepted 15 September 2006 Available online 9 November 2006 Abstract Particulate hexavalent chromium (Cr(VI)) is a known human lung carcinogen. Cr(VI)-induced tumors exhibit chromosome instability (CIN), but the mechanisms underlying these effects are unknown. We investigated a possible role for the Fanconi anemia (FA) pathway in particulate Cr(VI)-induced chromosomal damage by focusing on the Fancg gene, which plays an important role in cellular resistance to DNA interstrand crosslinks. We used the isogenic Chinese hamster ovary (CHO) KO40 fancg mutant compared with parental and gene-complemented cells. We found that fancg cells treated with lead chromate had lower intracellular Cr ion levels than control cell lines. Accounting for differences of Cr ion levels between cell lines, we discovered that fancg cells treated with lead chromate had increased cytotoxicity and chromosomal aberrations, which was not observed after restoring the Fancg gene. Chromosomal damage was manifest as increased total chromosome damage and percent metaphases with damage, specifically an increase in chromatid and isochromatid breaks. We conclude that Fancg protects cells from particulate Cr(VI)-induced cytotoxicity and chromosome damage, which is consistent with the known sensitivity of fancg cells to crosslinking damage and the ability of Cr(VI) to produce crosslinks. © 2006 Elsevier B.V. All rights reserved. Keywords: Hexavalent chromium (Cr(VI)); Lead chromate; FANCG; Fanconi anemia pathway; Chromosome instability (CIN) ∗ Corresponding author at: 178 Science Building, 96 Falmouth Street, Portland, ME 04103, USA. Tel.: +1 207 228 8050; fax: +1 207 228 8057. E-mail addresses: John.Wise@usm.maine.edu, john.wise@maine.edu (J.P. Wise Sr.). 1. Introduction Lung cancer is the most frequent cause of cancer deaths in both men and women in the United States [1]. One widely recognized human lung carcinogen is hexavalent chromium (Cr(VI)) [2]. Particulate Cr(VI) compounds are considered to be the more potent Cr(VI) species and have been shown to induce tumors in 1383-5718/$ – see front matter © 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.mrgentox.2006.09.005