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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 120-127 |
| Number of pages | 8 |
| Journal | Mutation Research - Genetic Toxicology and Environmental Mutagenesis |
| Volume | 626 |
| Issue number | 1-2 |
| DOIs | |
| State | Published - Jan 10 2007 |
| Externally published | Yes |
Fingerprint
Keywords
- Chromosome instability (CIN)
- FANCG
- Fanconi anemia pathway
- Hexavalent chromium (Cr(VI))
- Lead chromate
ASJC Scopus subject areas
- Health, Toxicology and Mutagenesis
- Genetics
Cite this
Role of the Fancg gene in protecting cells from particulate chromate-induced chromosome instability. / Savery, Laura C.; Grlickova-Duzevik, Eliza; Wise, Sandra S.; Thompson, W. Douglas; Hinz, John M.; Thompson, Larry H.; Wise, John Pierce.
In: Mutation Research - Genetic Toxicology and Environmental Mutagenesis, Vol. 626, No. 1-2, 10.01.2007, p. 120-127.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Role of the Fancg gene in protecting cells from particulate chromate-induced chromosome instability
AU - Savery, Laura C.
AU - Grlickova-Duzevik, Eliza
AU - Wise, Sandra S.
AU - Thompson, W. Douglas
AU - Hinz, John M.
AU - Thompson, Larry H.
AU - Wise, John Pierce
PY - 2007/1/10
Y1 - 2007/1/10
N2 - 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.
AB - 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.
KW - Chromosome instability (CIN)
KW - FANCG
KW - Fanconi anemia pathway
KW - Hexavalent chromium (Cr(VI))
KW - Lead chromate
UR - http://www.scopus.com/inward/record.url?scp=33845309627&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=33845309627&partnerID=8YFLogxK
U2 - 10.1016/j.mrgentox.2006.09.005
DO - 10.1016/j.mrgentox.2006.09.005
M3 - Article
VL - 626
SP - 120
EP - 127
JO - Mutation Research - Genetic Toxicology and Environmental Mutagenesis
JF - Mutation Research - Genetic Toxicology and Environmental Mutagenesis
SN - 1383-5718
IS - 1-2
ER -