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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.

SUBMITTER: Saha B

PROVIDER: S-EPMC4032596 | biostudies-literature | 2014 Jun

REPOSITORIES: biostudies-literature

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

Saha Bidisha B Cypro Alexander A Martin George M GM Oshima Junko J

Aging cell 20140205 3

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 ...[more]

PMID: 24308646

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