Role of the Fancg gene in protecting cells from particulate chromate-induced chromosome instability.
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.
Savery
Laura C
LC
Wise Laboratory of Environmental and Genetic Toxicology, University of Southern Maine, 96 Falmouth Street, P.O. Box 9300, Portland, ME 04104-9300, USA.
Grlickova-Duzevik
Eliza
E
Wise
Sandra S
SS
Thompson
W Douglas
WD
Hinz
John M
JM
Thompson
Larry H
LH
Wise
John Pierce
JP
D000818:Animals; D016466:CHO Cells; D002840:Chromates / Q000633:toxicity*; D043171:Chromosomal Instability; D006224:Cricetinae; D003412:Cricetulus; D052241:Fanconi Anemia Complementation Group G Protein / Q000235:genetics*; D006801:Humans; D007854:Lead / Q000633:toxicity*; D009153:Mutagens / Q000633:toxicity*
D002840:Chromates; C499909:FANCG protein, human; D052241:Fanconi Anemia Complementation Group G Protein; D009153:Mutagens; D007854:Lead; C031895:lead chromate