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Carcinogenesis Advance Access originally published online on May 27, 2004
Carcinogenesis 2004 25(10):1821-1827; doi:10.1093/carcin/bgh191
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Carcinogenesis vol.25 no.10 © Oxford University Press 2004; all rights reserved.

ARTICLE

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

Leah C. Young1, Kyle J. Thulien1, Marcia R. Campbell1, Victor A. Tron2,3 and Susan E. Andrew1,2,4

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

4 To whom correspondence should be addressed Email: susan.andrew{at}ualberta.ca

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 cellular responses to exogenous DNA damage that does not involve removal of DNA adducts. We have demonstrated previously that both Msh2- and Msh6-null primary mouse embryonic fibroblasts are significantly less sensitive to UVB (ultraviolet B)-induced cytotoxicity and apoptosis than wild-type control cells. In order to ascertain the physiological relevance of the 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-h 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 wild-type 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.


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Home page
 MutagenesisHome page
P. Pitsikas, D. Lee, and A. J. Rainbow
Reduced host cell reactivation of oxidative DNA damage in human cells deficient in the mismatch repair gene hMSH2
Mutagenesis, May 1, 2007; 22(3): 235 - 243.
[Abstract] [Full Text] [PDF]


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