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 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.
Young
Leah C
LC
Department of Medical Genetics, University of Alberta, Edmonton, Alberta, Canada.
Thulien
Kyle J
KJ
Campbell
Marcia R
MR
Tron
Victor A
VA
Andrew
Susan E
SE
D000818:Animals; D017209:Apoptosis / Q000528:radiation effects*; D002294:Carcinoma, Squamous Cell / Q000378:metabolism / Q000473:pathology; D018736:DNA Adducts; D004260:DNA Repair / Q000528:radiation effects*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D000078404:Epidermal Cells; D004817:Epidermis / Q000502:physiology / Q000528:radiation effects*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D018895:Microsatellite Repeats; D051718:MutS Homolog 2 Protein; D009361:Neoplasm Invasiveness / Q000473:pathology; D009381:Neoplasms, Radiation-Induced / Q000378:metabolism / Q000473:pathology*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000502:physiology*; D011740:Pyrimidine Dimers; D012878:Skin Neoplasms / Q000378:metabolism / Q000473:pathology*; D014466:Ultraviolet Rays
D018736:DNA Adducts; D004268:DNA-Binding Proteins; C102997:Msh6 protein, mouse; D011518:Proto-Oncogene Proteins; D011740:Pyrimidine Dimers; C497172:MSH2 protein, human; C497173:Msh2 protein, mouse; D051718:MutS Homolog 2 Protein