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Molecular and Cellular Biology, May 2005, p. 3596-3607, Vol. 25, No. 9
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.9.3596-3607.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Mismatch Repair Proteins Are Activators of Toxic Responses to Chromium-DNA Damage

Elizabeth Peterson-Roth, Mindy Reynolds, George Quievryn, and Anatoly Zhitkovich*

Department of Pathology and Laboratory Medicine, Brown University, Providence, Rhode Island

Received 27 October 2004/ Returned for modification 23 November 2004/ Accepted 8 February 2005

Chromium(VI) is a toxic and carcinogenic metal that causes the formation of DNA phosphate-based adducts. Cr-DNA adducts are genotoxic in human cells, although they do not block replication in vitro. Here, we report that induction of cytotoxicity in Cr(VI)-treated human colon cells and mouse embryonic fibroblasts requires the presence of all major mismatch repair (MMR) proteins. Cr-DNA adducts lost their ability to block replication of Cr-modified plasmids in human colon cells lacking MLH1 protein. The presence of functional mismatch repair caused induction of p53-independent apoptosis associated with activation of caspases 2 and 7. Processing of Cr-DNA damage by mismatch repair resulted in the extensive formation of {gamma}-H2AX foci in G2 phase, indicating generation of double-stranded breaks as secondary toxic lesions. Induction of {gamma}-H2AX foci was observed at 6 to 12 h postexposure, which was followed by activation of apoptosis in the absence of significant G2 arrest. Our results demonstrate that mismatch repair system triggers toxic responses to Cr-DNA backbone modifications through stress mechanisms that are significantly different from those for other forms of DNA damage. Selection for Cr(VI) resistant, MMR-deficient cells may explain the very high frequency of lung cancers with microsatellite instability among chromate workers.

* Corresponding author. Mailing address: Brown University, Pathology and Laboratory Medicine, 70 Ship St., Box G-E507, Providence, RI 02912. Phone: (401) 863-2912. Fax: (401) 863-9008. E-mail: anatoly_zhitkovich{at}brown.edu.

Molecular and Cellular Biology, May 2005, p. 3596-3607, Vol. 25, No. 9
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.9.3596-3607.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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