Mismatch repair protein Msh2 contributes to UVB-induced cell cycle arrest in epidermal and cultured mouse keratinocytes.
Nucleotide excision repair (NER), cell cycle regulation and apoptosis are major defence mechanisms against the carcinogenic effects of UVB radiation. NER eliminates UVB-induced DNA photolesions via two subpathways: global genome repair (GGR) and transcription-coupled repair (TCR). In a previous study, we found UVB-induced accumulation of tetraploid (4N) keratinocytes in the epidermis of Xpc(-/-) mice (no GGR), but not in Xpa(-/-) (no TCR and no GGR) or in wild-type (WT) mice. We inferred that this arrest in Xpc(-/-) mice is caused by erroneous replication past photolesions, leading to 'compound lesions' known to be recognised by mismatch repair (MMR). MMR-induced futile cycles of breakage and resynthesis at sites of compound lesions may then sustain a cell cycle arrest. The present experiments with Xpc(-/-)Msh2(-/-) mice and derived keratinocytes show that the MMR protein Msh2 indeed plays a role in the generation of the UVB-induced arrested cells: a Msh2-deficiency lowered significantly the percentage of arrested cells in vivo (40-50%) and in vitro (30-40%). Analysis of calyculin A (CA)-induced premature chromosome condensation (PCC) of cultured Xpc(-/-) keratinocytes showed that the delayed arrest occurred in late S phase rather than in G(2)-phase. Taken together, the results indicate that in mouse epidermis and cultured keratinocytes, the MMR protein Msh2 plays a role in the UVB-induced S-phase arrest. This indicates that MMR plays a role in the UVB-induced S-phase arrest. Alternatively, Msh2 may have a more direct signalling function.
van Oosten
Marijke
M
Department of Toxicogenetics, Leiden University Medical Center, Wassenaarseweg 72, 2333 AL Leiden, The Netherlands.
Stout
Gerdine J
GJ
Backendorf
Claude
C
Rebel
Heggert
H
de Wind
Niels
N
Darroudi
Firouz
F
van Kranen
Henk J
HJ
de Gruijl
Frank R
FR
Mullenders
Leon Hf
LH
D000818:Animals; D020137:Base Pair Mismatch / Q000235:genetics*; D001973:Bromodeoxyuridine; D002453:Cell Cycle / Q000235:genetics / Q000528:radiation effects*; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000235:genetics*; D005434:Flow Cytometry; D015603:Keratinocytes / Q000502:physiology; D008387:Marine Toxins; D051379:Mice; D008817:Mice, Mutant Strains; D051718:MutS Homolog 2 Protein; D010080:Oxazoles; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D014466:Ultraviolet Rays
D004268:DNA-Binding Proteins; D008387:Marine Toxins; D010080:Oxazoles; D011518:Proto-Oncogene Proteins; C059041:calyculin A; C497173:Msh2 protein, mouse; D051718:MutS Homolog 2 Protein; D001973:Bromodeoxyuridine