The DNA-mismatch repair enzyme hMSH2 modulates UV-B-induced cell cycle arrest and apoptosis in melanoma cells.
The mechanisms by which the post-replicative DNA mismatch repair (MMR) enzyme MSH2 is involved in the complex response mechanisms to UV damage are yet to be clarified. Here, we show increased levels of MSH2 mRNA in malignant melanoma, metastases of melanoma, and melanoma cell (MeWo) lines as compared with melanocytic nevi or primary cultured benign melanocytes. UV-B treatment modulated MSH2 expression and silencing of MSH2 gene expression using small interfering RNA technology regulated UV-B-induced cell cycle arrest and apoptosis in human MeWo. We show that MSH2-deficient non-malignant mouse fibroblasts (MEF-/-) are partially resistant against UV-B-induced apoptosis and show reduced S-Phase accumulation. In addition, we show that an Msh2 point mutation (MEFGA) that affects MMR does not affect UV-B-induced apoptosis. In conclusion, we demonstrate that MSH2 modulates in human melanocytes both UV-B-induced cell cycle regulation and apoptosis, most likely via independent, uncoupled mechanisms.
Seifert
Markus
M
Department of Dermatology, The Saarland University Hospital, Homburg, Germany. hgmsei@uniklinik-saarland.de
Scherer
Stefan J
SJ
Edelmann
Wilfried
W
Böhm
Markus
M
Meineke
Viktor
V
Löbrich
Markus
M
Tilgen
Wolfgang
W
Reichrath
Jörg
J
D048868:Adaptor Proteins, Signal Transducing / Q000502:physiology; D017209:Apoptosis / Q000528:radiation effects*; D002453:Cell Cycle / Q000528:radiation effects*; D045744:Cell Line, Tumor; D053843:DNA Mismatch Repair; D006657:Histones / Q000378:metabolism; D006801:Humans; D008544:Melanocytes / Q000528:radiation effects; D008545:Melanoma / Q000473:pathology* / Q000556:secondary; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D009154:Mutation; D009687:Nuclear Proteins / Q000502:physiology; D010766:Phosphorylation; D012333:RNA, Messenger / Q000032:analysis; D034741:RNA, Small Interfering / Q000235:genetics; D014162:Transfection; D014466:Ultraviolet Rays
D048868:Adaptor Proteins, Signal Transducing; C468783:H2AX protein, human; D006657:Histones; C501486:MLH1 protein, human; D009687:Nuclear Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein