The Werner syndrome protein is a DNA helicase

Abstract

Werner syndrome (WS) is an uncommon autosomal recessive disorder characterized by premature aging. The clinical manifestations of WS, including atherosclerosis and osteoporosis, appear early in adulthood, and death in the fourth to sixth decade commonly ensues from myocardial infarction or cancer. In accord with the aging phenotype, cells from WS patients have a reduced replicative life span in culture. Genomic instability is observed at the cytogenetic level in the form of chromosome breaks and translocations and at the molecular level by multiple large deletions. The Werner syndrome gene (WRN) has recently been cloned. The predicted product is a 1,432-amino-acid protein whose central domain is homologous to members of the RecQ family of DNA helicases. Such homology does not necessarily mean that WRN encodes an active helicase. For example, the Saccharomyces cerevisiae RAD26 gene protein and the human transcription-repair coupling factor CSB (Cockayne syndrome 8) are highly homologous to known helicases, yet neither encodes an active helicase. Moreover, the Bloom's syndrome gene (BLM), discovered before WRN, is also homologous to the RecQ family of DNA helicases, though we still await demonstration that it encodes an active helicase. Here we report that the WS protein does indeed catalyze DNA unwinding.

The Werner syndrome protein has separable recombination and survival functions☆

“…1A). The missense mutations used had been previously shown to inactivate the WRN helicase or exonuclease activity [16,17]. A myc epitope tag was added in-frame to the N-terminus of all of the WRN proteins to allow unambiguous detection of transgene-encoded proteins in the presence of native WRN (Fig.…”

DNA repair, genome stability and cancer: a historical perspective

“…However the penetrance of such polymorphisms is weak and the clinical relevance of these to the overall cancer burden was unclear 30 . Subsequently several complex conditions in which cancer predisposition is a feature, such as Bloom's and Werner's syndromes, and Fanconi anaemia, have been shown to arise from genetic defects in DNA repair systems, as have subsets of familial breast, ovarian, prostate and pancreatic cancers [31][32][33][34][35][36] .…”

Cancer and aging: the importance of telomeres in genome maintenance

“…TRF2 also interacts with the DNA damage sensing protein ATM, and is thought to inhibit ATM activity specifically at telomeres [81], and WRN [82], the protein that is defective in the human premature aging and cancer-prone disorder Werner syndrome [83,84]. WRN encodes a DNA helicase and exonuclease [85,86] that appears to participate in both the NHEJ and HR DNA repair pathways [87][88][89][90][91][92][93][94]. It is not known whether all TRF1 complexes contain TANK1/2 and/or Ku, or whether all TRF2 complexes contain ATM, WRN, the RMN complex and/or other DNA damage sensors or repair proteins (Fig.…”