title: Mismatch repair protein Msh2 contributes to UVB-induced cell cycle arrest in epidermal and cultured mouse keratinocytes.
abstract: 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.
authors.affiliation: Department of Toxicogenetics, Leiden University Medical Center, Wassenaarseweg 72, 2333 AL Leiden, The Netherlands.
authors.forename: Marijke
authors.initials: M
authors.lastname: van Oosten
authors.forename: Gerdine J
authors.initials: GJ
authors.lastname: Stout
authors.forename: Claude
authors.initials: C
authors.lastname: Backendorf
authors.forename: Heggert
authors.initials: H
authors.lastname: Rebel
authors.forename: Niels
authors.initials: N
authors.lastname: de Wind
authors.forename: Firouz
authors.initials: F
authors.lastname: Darroudi
authors.forename: Henk J
authors.initials: HJ
authors.lastname: van Kranen
authors.forename: Frank R
authors.initials: FR
authors.lastname: de Gruijl
authors.forename: Leon Hf
authors.initials: LH
authors.lastname: Mullenders
mesh_terms: 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
chemical_list: 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