title: Mismatch repair in extracts of Werner syndrome cell lines.
abstract: Werner syndrome (WS) is an autosomal recessive disease, the phenotype of which is a caricature of premature aging. WS cells and cell lines display several types of genetic instability, and WS patients have an increased risk of developing cancer. The WS locus (WRN) encodes a protein that shows significant sequence homology to the RecQ family of DNA helicases. Because a DNA helicase may function in DNA mismatch repair, we examined extracts of WS cell lines for mismatch repair activity. Extracts from four different WS lymphoblastoid cell lines containing different WRN mutations and from three within-pedigree control cell lines were all proficient in mismatch repair. In marked contrast, extracts from three independent WS fibroblastoid cell lines were deficient in repair of base-base and insertion/deletion mismatches. Extracts of one of these lines restored activity to extracts of mismatch repair-deficient tumor cells with defined mutations in hMSH2, hMSH3, hMSH6, hMLH1, or hPMS2. This suggests that the WRN mutation in this fibroblast line is not a dominant negative inhibitor of mismatch repair activity and that the repair defect does not reside in these five known mismatch repair genes. Defective mismatch repair in fibroblastoid but not lymphoblastoid cells is consistent with the possibility that WRN protein could have a cell type- and/or tissue-specific role in mismatch repair. Alternatively, a mutation in WRN could predispose cells to mutations in other genes required for mismatch repair activity, at least one of which could be an unknown gene.
authors.affiliation: Laboratory of Molecular Genetics, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA.
authors.forename: S E
authors.initials: SE
authors.lastname: Bennett
authors.forename: A
authors.initials: A
authors.lastname: Umar
authors.forename: J
authors.initials: J
authors.lastname: Oshima
authors.forename: R J
authors.initials: RJ
authors.lastname: Monnat
authors.forename: T A
authors.initials: TA
authors.lastname: Kunkel
mesh_terms: D002460:Cell Line; D004265:DNA Helicases / Q000502:physiology*; D004260:DNA Repair; D005090:Exodeoxyribonucleases; D005816:Genetic Complementation Test; D006801:Humans; D053484:RecQ Helicases; D014898:Werner Syndrome / Q000235:genetics*; D000071657:Werner Syndrome Helicase
chemical_list: D005090:Exodeoxyribonucleases; D004265:DNA Helicases; D053484:RecQ Helicases; C098785:WRN protein, human; D000071657:Werner Syndrome Helicase