MISMATCH REPAIR IN EXTRACTS OF WERNER SYNDROME CELL-LINES

Werner syndrome (WS) is an autosomal recessive disease, the phenotype of which is a caricature of premature aging, WS cells and cell lines d isplay several types of genetic instability, and WS patients have an i ncreased risk of developing cancer, The WS locus (WRN) encodes a prote in that shows significant sequence homology to the RecQ family of DNA helicases, Because a DNA helicase may function in DIVA mismatch repair , we examined extracts of WS cell lines for mismatch repair activity, Extracts from four different WS lymphoblastoid cell lines containing d ifferent WRN mutations and from three within-pedigree control cell lin es were all proficient in mismatch repair, In marked contrast, extract s from three independent WS fibroblastoid cell lines were deficient in repair of base-base and insertion/deletion mismatches, Extracts of on e of these lines restored activity to extracts of mismatch repair-defi cient tumor cells with defined mutations in hMSH2, hMSH3, hMSH6, hMLH1 , or hPMS2. This suggests that the WRN mutation in this fibroblast lin e is not a dominant negative inhibitor of mismatch repair activity and that the repair defect does not reside in these five known mismatch r epair genes, Defective mismatch repair in fibroblastoid but not lympho blastoid cells is consistent with the possibility that WRN protein cou ld have a cell type- and/or tissue-specific role in mismatch repair. A lternatively, a mutation in WRN could predispose cells to mutations in other genes required for mismatch repair activity, at least one of wh ich could be an unknown gene.