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

• Published in: Carcinogenesis (New York) 2004-10, Vol.25 (10), p.1821-1827
• Main Authors: Young, Leah C., Thulien, Kyle J., Campbell, Marcia R., Tron, Victor A., Andrew, Susan E.
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis - radiation effects; Biological and medical sciences; Carcinogenesis, carcinogens and anticarcinogens; Carcinoma, Squamous Cell - metabolism; Carcinoma, Squamous Cell - pathology; DNA Adducts; DNA mismatch repair; DNA Repair - radiation effects; DNA-Binding Proteins - genetics; DNA-Binding Proteins - physiology; Epidermis - cytology; Epidermis - physiology; Epidermis - radiation effects; Humans; Medical sciences; MEF; Mice; Mice, Knockout; microsatellite instability; Microsatellite Repeats; MMR; mouse embryonic fibroblast; MSI; MutS Homolog 2 Protein; Neoplasm Invasiveness - pathology; Neoplasms, Radiation-Induced - metabolism; Neoplasms, Radiation-Induced - pathology; NER; nucleotide excision repair; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - physiology; Pyrimidine Dimers; SBC; SCC; Skin Neoplasms - metabolism; Skin Neoplasms - pathology; squamous cell carcinoma; sunburn cells or apoptotic epidermal cells; TCR; transcription coupled repair; Tumors; ultraviolet; ultraviolet radiation between 280 and 315 nm; Ultraviolet Rays; UVB; xeroderma pigmentosum A; XPA
• ISSN: 0143-3334; 1460-2180; 1460-2180
• DOI: 10.1093/carcin/bgh191

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.