This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Peterson-Roth, E.
Right arrow Articles by Zhitkovich, A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Peterson-Roth, E.
Right arrow Articles by Zhitkovich, A.

 Previous Article  |  Next Article 

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.



This article has been cited by other articles:

  • Peterson-Roth, E., Brdlik, C. M., Glazer, P. M. (2009). Src-Induced Cisplatin Resistance Mediated by Cell-to-Cell Communication. Cancer Res. 69: 3619-3624 [Abstract] [Full Text]  
  • Reynolds, M. F., Peterson-Roth, E. C., Bespalov, I. A., Johnston, T., Gurel, V. M., Menard, H. L., Zhitkovich, A. (2009). Rapid DNA Double-Strand Breaks Resulting from Processing of Cr-DNA Cross-Links by Both MutS Dimers. Cancer Res. 69: 1071-1079 [Abstract] [Full Text]  
  • Reynolds, M., Zhitkovich, A. (2007). Cellular vitamin C increases chromate toxicity via a death program requiring mismatch repair but not p53. Carcinogenesis 28: 1613-1620 [Abstract] [Full Text]  
  • Hou, Y., Gao, F., Wang, Q., Zhao, J., Flagg, T., Zhang, Y., Deng, X. (2007). Bcl2 Impedes DNA Mismatch Repair by Directly Regulating the hMSH2-hMSH6 Heterodimeric Complex. J. Biol. Chem. 282: 9279-9287 [Abstract] [Full Text]  
  • Reynolds, M., Stoddard, L., Bespalov, I., Zhitkovich, A. (2007). Ascorbate acts as a highly potent inducer of chromate mutagenesis and clastogenesis: linkage to DNA breaks in G2 phase by mismatch repair. Nucleic Acids Res 35: 465-476 [Abstract] [Full Text]  
  • Quievryn, G., Messer, J., Zhitkovich, A. (2006). Lower mutagenicity but higher stability of Cr-DNA adducts formed during gradual chromate activation with ascorbate. Carcinogenesis 27: 2316-2321 [Abstract] [Full Text]  
  • Daikoku, T., Kudoh, A., Sugaya, Y., Iwahori, S., Shirata, N., Isomura, H., Tsurumi, T. (2006). Postreplicative Mismatch Repair Factors Are Recruited to Epstein-Barr Virus Replication Compartments. J. Biol. Chem. 281: 11422-11430 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»