Rapamycin decreases DNA damage accumulation and enhances cell growth of WRN‐deficient human fibroblasts

• Published in: Aging cell Vol. 13; no. 3; pp. 573 - 575
• Main Authors: Saha, Bidisha, Cypro, Alexander, Martin, George M., Oshima, Junko
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01.06.2014; BlackWell Publishing Ltd
• Subjects: Autophagy; Cell Cycle - drug effects; Cell Growth Processes - drug effects; Deoxyribonucleic acid; DNA; DNA damage; DNA Damage - drug effects; Exodeoxyribonucleases - deficiency; Fibroblasts - cytology; Fibroblasts - drug effects; Fibroblasts - metabolism; Growth; Humans; mammalian target of rapamycin; Mutation; Proteins; Rapamycin; RecQ Helicases - deficiency; Short Takes; Sirolimus - pharmacology; Werner syndrome; Werner Syndrome - genetics; Werner Syndrome - metabolism; Werner Syndrome - pathology; Werner Syndrome Helicase; mammalian target of rapamycin; autophagy; Werner syndrome; DNA damage; rapamycin
• ISSN: 1474-9718; 1474-9726
• DOI: 10.1111/acel.12190

Summary 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.