DNA Mismatch Repair Protein Msh6 Is Required for Optimal Levels of Ultraviolet-B-Induced Apoptosis in Primary Mouse Fibroblasts

• Published in: Journal of investigative dermatology Vol. 121; no. 4; pp. 876 - 880
• Main Authors: Young, Leah C., Peters, Anthea C., Maeda, Tomoko, Edelmann, Winfried, Kucherlapati, Raju, Andrew, Susan E., Tron, Victor A.
• Format: Journal Article
• Language: English
• Published: Danvers, MA Elsevier Inc 01.10.2003; Nature Publishing; Elsevier Limited
• Subjects: Animals; apoptosis; Apoptosis - physiology; Apoptosis - radiation effects; Biological and medical sciences; Biological effects of radiation; Cell Survival - physiology; Cell Survival - radiation effects; Cells, Cultured; cytotoxicity; DNA mismatch repair; DNA Repair - physiology; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Fibroblasts - cytology; Fibroblasts - physiology; Fibroblasts - radiation effects; Fundamental and applied biological sciences. Psychology; Mice; Mice, Knockout; Msh6; Non ionizing radiations. Hertzian waves. Biooptics; Skin Neoplasms - prevention & control; Tissues, organs and organisms biophysics; Tumor Suppressor Protein p53 - genetics; ultraviolet B; Ultraviolet Rays - adverse effects; Msh6; apoptosis; ultraviolet B; cytotoxicity; DNA mismatch repair; UVB radiation; Rodentia; In vitro; Protein; apoptosis/cytotoxicity/DNA mismatch repair/Msh6/ultraviolet B; Vertebrata; Mammalia; Mouse; Animal; DNA; Biological effect; Fibroblast; Apoptosis
• ISSN: 0022-202X; 1523-1747
• DOI: 10.1046/j.1523-1747.2003.12486.x

Recent data support a role for DNA mismatch repair in the cellular response to some forms of exogenous DNA damage beyond that of DNA repair; cells with defective DNA mismatch repair have partial or complete failure to undergo apoptosis and/or G2M arrest following specific types of damage. We propose that the DNA mismatch repair Msh2/Msh6 heterodimer, responsible for the detection of DNA damage, promotes apoptosis in normal cells, thus protecting mammals from ultraviolet-induced malignant transformation. Using primary mouse embryonic fibroblasts derived from Msh6+/+ and Msh6–/– mice, we compare the response of DNA-mismatch repair-proficient and -deficient cells to ultraviolet B radiation. In the wild-type mouse embryonic fibroblasts, ultraviolet-B-induced increases in Msh6 protein levels were not dependent on p53. Msh6–/– mouse embryonic fibroblasts were significantly less sensitive to the cytotoxic effects of ultraviolet B radiation. Further comparison of the Msh6+/+ and Msh6–/– mouse embryonic fibroblasts revealed that Msh6–/– mouse embryonic fibroblasts undergo significantly less apoptosis following ultraviolet B irradiation, thus indicating that ultraviolet-B-induced apoptosis is partially Msh6 dependent. These data support a role for Msh6 in protective cellular responses of primary cells to ultraviolet-B-induced mutagenesis and, hence, the prevention of skin cancer.