DNA mismatch repair proteins promote apoptosis and suppress tumorigenesis in response to UVB irradiation: an in vivo study
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 re...
Saved in:
Published in | Carcinogenesis (New York) Vol. 25; no. 10; pp. 1821 - 1827 |
---|---|
Main Authors | , , , , |
Format | Journal Article |
Language | English |
Published |
Oxford
Oxford University Press
01.10.2004
Oxford Publishing Limited (England) |
Subjects | |
Online Access | Get full text |
Cover
Loading…
Summary: | 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. |
---|---|
Bibliography: | ark:/67375/HXZ-CTX18XT1-V local:bgh191 istex:4E116E42A750AEA7F89FA22AB45D1FAAA3A842F0 4To whom correspondence should be addressed Email: susan.andrew@ualberta.ca ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 |
ISSN: | 0143-3334 1460-2180 1460-2180 |
DOI: | 10.1093/carcin/bgh191 |