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Carcinogenesis Advance Access published online on May 27, 2004
Carcinogenesis, doi:10.1093/carcin/bgh191
© 2004 by Oxford University Press
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Received November 25, 2003
Revised May 3, 2004
Accepted May 16, 2004

CANCER BIOLOGY

DNA mismatch repair proteins promote apoptosis and suppress tumorigenesis in response to UVB irradiation: an in vivo study

Leah C. Young 1, Kyle J. Thulien 1, Marcia R. Campbell 1, Victor A. Tron 2, Susan E. Andrew 3*

1 Department of Medical Genetics, University of Alberta, Edmonton, Alberta, Canada
2 Department of Experimental Oncology, University of Alberta, Edmonton, Alberta, Canada; Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Alberta, Canada
3 Department of Medical Genetics, University of Alberta, Edmonton, Alberta, Canada; Department of Experimental Oncology, University of Alberta, Edmonton, Alberta, Canada

* To whom correspondence should be addressed. E-mail: susan.andrew{at}ualberta.ca.


  Abstract

DNA mismatch repair (MMR) proteins are integral to the maintenance of genomic stability and suppression of tumorigenesis due to their role in repair of post-replicative DNA errors. Recent data also support a role for MMR proteins in the cellular responses to exogenous DNA damage that does not involve removal of DNA adducts. We have previously demonstrated that both Msh2- and Msh6-null primary mouse embryonic fibroblasts are significantly less sensitive to UVB-induced cytotoxicity and apoptosis than wildtype control cells. In order to ascertain the physiological relevance of these data we have exposed MMR-deficient mice to acute and chronic UVB radiation. We found that MMR-deficiency was associated with reduced levels of apoptosis and increased residual UVB-induced DNA adducts in the epidermis 24 hours following acute UVB exposure. Moreover, Msh2-null mice developed UVB-induced skin tumors at a lower level of cumulative UVB exposure and with a greater severity of onset than wildtype mice. The Msh2-null skin tumors did not display microsatellite instability, suggesting that these tumors develop via a different tumorigenic pathway than tumors that develop spontaneously. Therefore, we propose that dysfunctional MMR promotes UVB induced tumorigenesis through reduced apoptotic elimination of damaged epidermal cells.

Key Words: DNA mismatch repair, apoptosis, UVB, skin cancer


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