DNA mismatch repair protein Msh6 is required for optimal levels of ultraviolet-B-induced apoptosis in primary mouse fibroblasts.
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.
Young
Leah C
LC
Department of Medical Genetics, University of Alberta, Edmonton, Alberta, Canada.
Peters
Anthea C
AC
Maeda
Tomoko
T
Edelmann
Winfried
W
Kucherlapati
Raju
R
Andrew
Susan E
SE
Tron
Victor A
VA
D000818:Animals; D017209:Apoptosis / Q000502:physiology* / Q000528:radiation effects; D002470:Cell Survival / Q000502:physiology / Q000528:radiation effects; D002478:Cells, Cultured; D004260:DNA Repair / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology* / Q000528:radiation effects; D051379:Mice; D018345:Mice, Knockout; D012878:Skin Neoplasms / Q000517:prevention & control; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D014466:Ultraviolet Rays / Q000009:adverse effects
D004268:DNA-Binding Proteins; C094443:G-T mismatch-binding protein; C102997:Msh6 protein, mouse; D016159:Tumor Suppressor Protein p53