Journal Article

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

Leah C. Young, Kyle J. Thulien, Marcia R. Campbell, Victor A. Tron and Susan E. Andrew

in Carcinogenesis

Volume 25, issue 10, pages 1821-1827
Published in print October 2004 | ISSN: 0143-3334
Published online October 2004 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgh191
DNA mismatch repair proteins promote apoptosis and suppress tumorigenesis in response to UVB irradiation: an in vivo study

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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.

Keywords: MEF, mouse embryonic fibroblast; MMR, DNA mismatch repair; MSI, microsatellite instability; NER, nucleotide excision repair; SBC, sunburn cells or apoptotic epidermal cells; SCC, squamous cell carcinoma; TCR, transcription coupled repair; UV, ultraviolet; UVB, ultraviolet radiation between 280 and 315 nm; XPA, xeroderma pigmentosum A

Journal Article.  5423 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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