title: Rapamycin decreases DNA damage accumulation and enhances cell growth of WRN-deficient human fibroblasts.
abstract: Werner syndrome (WS), caused by mutations at the WRN helicase gene, is a progeroid syndrome characterized by multiple features consistent with accelerated aging. Aberrant double-strand DNA damage repair leads to genomic instability and reduced replicative lifespan of somatic cells. We observed increased autophagy in WRN knockdown cells; this was further increased by short-term rapamycin treatment. Long-term rapamycin treatment resulted in improved growth rate, reduced accumulation of DNA damage foci and improved nuclear morphology; autophagy markers were reduced to near-normal levels, possibly due to clearance of damaged proteins. These data suggest that protein aggregation plays a role in the development of WS phenotypes and that the mammalian target of rapamycin complex 1 pathway is a potential therapeutic target of WS.
authors.affiliation: Department of Pathology, University of Washington, Seattle, WA, USA.
authors.forename: Bidisha
authors.initials: B
authors.lastname: Saha
authors.forename: Alexander
authors.initials: A
authors.lastname: Cypro
authors.forename: George M
authors.initials: GM
authors.lastname: Martin
authors.forename: Junko
authors.initials: J
authors.lastname: Oshima
mesh_terms: D002453:Cell Cycle / Q000187:drug effects; D048708:Cell Growth Processes / Q000187:drug effects; D004249:DNA Damage / Q000187:drug effects*; D005090:Exodeoxyribonucleases / Q000172:deficiency*; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D053484:RecQ Helicases / Q000172:deficiency*; D020123:Sirolimus / Q000494:pharmacology*; D014898:Werner Syndrome / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000071657:Werner Syndrome Helicase
chemical_list: D005090:Exodeoxyribonucleases; D053484:RecQ Helicases; C098785:WRN protein, human; D000071657:Werner Syndrome Helicase; D020123:Sirolimus
keywords: DNA damage; Werner syndrome; autophagy; mammalian target of rapamycin; rapamycin