Carcinogenesis Advance Access published online on July 29, 2004
Carcinogenesis, doi:10.1093/carcin/bgh242
© 2004 by Oxford University Press
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1 Department of Pharmacology and Physiology, The George Washington University Medical Center, 2300 I Street, NW, Washington DC, 20037; Program in Molecular and Cellular Oncology, The George Washington University Medical Center, 2300 I Street, NW, Washington DC, 20037
* To whom correspondence should be addressed. E-mail: phmsrp{at}gwumc.edu.
Certain hexavalent chromium [Cr(VI)] compounds are implicated as occupational respiratory carcinogens. Cr(VI) induces a broad spectrum of DNA damage, but Cr(VI)-induced DNA double strand breaks (DSBs) have not been reported. Previously, we found that Cr(VI) activates the ataxia telangiectasia mutated (ATM) kinase. ATM is activated specifically in response to DSBs. Therefore, the objective of this study was to investigate DSB induction by Cr(VI) exposure with the overarching hypothesis that S phase-dependent DSBs are produced by Cr(VI) exposure. To test this hypothesis, normal human fibroblasts were treated with either Cr(VI) or neocarzinostatin (NCS). DSBs were analyzed by both comet assay under neutral conditions, which detects primarily DNA DSBs, and phosphorylation of histone H2AX (
Revised July 14, 2004
Accepted July 18, 2004
CARCINOGENESIS
Generation of S phase-dependent DNA double strand breaks by Cr(VI) exposure: involvement of ATM in Cr(VI) induction of
-H2AX
2 Department of Pharmacology and Physiology, The George Washington University Medical Center, 2300 I Street, NW, Washington DC, 20037; Program in Molecular and Cellular Oncology, The George Washington University Medical Center, 2300 I Street, NW, Washington DC, 20037; The George Washington University Cancer Institute, The George Washington University Medical Center, 2300 I Street, NW, Washington DC, 20037
Abstract 
-H2AX) and the resultant formation of nuclear foci, which are considered to be indicative of DSBs. Induction of DSBs was observed after Cr(VI) exposure, however, the Cr(VI)-induced DSBs were abrogated by G1 synchronization. Furthermore, our data showed that Cr(VI)-induced DSBs were only observed in the S-phase population, whereas no significant DSBs were observed in Cr(VI)-treated G1 synchronized cells. In contrast, NCS-induced DSBs were equally distributed in all cell cycle phases in both asynchronous and G1-synchronized cells. Moreover, Cr(VI)-induced -H2AX foci formation was restricted to PCNA-positive cells, whereas, NCS-induced -H2AX foci formed in both PCNA-positive and -negative cells. These results indicate that Cr(VI)-induced DSBs are S phase-dependent. Finally, our data showed that Cr(VI)-induced -H2AX production was significantly decreased in ATM-/-cells compared to ATM-/- cells. Taken together, these results suggest that Cr(VI)-induced activation of ATM involves the formation of S phase-dependent DSBs. Examining the mechanism of Cr(VI)-induced DSBs will aid in understanding the interrelated mechanisms of Cr(VI) toxicity and carcinogenesis.
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