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SIRT1 contributes to telomere maintenance and augments global homologous recombination

2015-01-13

SIRT1 contributes to telomere maintenance and augments global homologous recombination "C:\Users\kurtw_000\Box Sync\DocDR\2014\02-03-2014d1015\SIRT1 contributes to telomere maintenance and augments global homologous recombination.pdf" Abstract Yeast Sir2 deacetylase is a component of the silent information regulator (SIR) complex encompassing Sir2/Sir3/Sir4. Sir2 is recruited to telomeres through Rap1, and this complex spreads into subtelomeric DNA via histone deacetylation. However, potential functions at telomeres for SIRT1, the mammalian orthologue of yeast Sir2, are less clear. We studied both loss of function (SIRT1 deficient) and gain of function (SIRT1super) mouse models. Our results indicate that SIRT1 is a positive regulator of telomere length in vivo and attenuates telomere shortening associated with aging, an effect dependent on telomerase activity. Using chromatin immunoprecipitation assays, we find that SIRT1 interacts with telomeric repeats in vivo. In addition, SIRT1 overexpression increases homologous recombination throughout the entire genome, including telomeres, centromeres, and chromosome arms. These findings link SIRT1 to telomere biology and global DNA repair and provide new mechanistic explanations for the known functions of SIRT1 in protection from DNA damage and some age-associated pathologies. some notes -We studied both loss of function (SIRT1 deficient) and gain of function (SIRT1 super ) mouse models - SIRT1 is a positive regulator of telomere length in vivo and attenuates telomere shortening associated with aging -SIRT1 overexpression increases homologous recombination throughout the entire genome -SIRT1 levels influence telomere length in mouse embryonic fibroblasts (MEFs) -Increased SIRT1 expression attenuates telomere erosion with age in adult tissues -SIRT1 effects on telomere length are largely dependent on telomerase activity -Increased SIRT1 expression augments homologous recombination at telomeres, centromeres, and chromosome arms -SIRT1 deficiency triggers a DNA damage response at chromosome ends -SIRT1 prevents telomere fragility -SIRT1-mediated deacetylation of telomeric and pericentromeric regions -SIRT1 specifically binds to telomeric repeats in vivo in induced pluripotent stem (iPS) cells -However, the molecular mechanisms by which SIRT1 impacts on CR, lifespan, and health span are still largely un- known -In summary, the findings described in this study demon - strate that increased expression of SIRT1, the closest mam- malian orthologue of yeast Sir2, improves telomere length maintenance in vivo and significantly increases recombination frequencies at telomeres, centromeres, and chromosome arms -cell culture -TRAP assay -immunoblotting -immunofluorescence -Q-FISH -TRF analysis -B1-SINE Cobra analysis for global DNA methylation -ChIP assay -CO-FISH
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