title: SIRT1 contributes to telomere maintenance and augments global homologous recombination.
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 (SIRT1(super)) 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.
authors.affiliation: Telomeres and Telomerase Group, Spanish National Cancer Centre, Madrid E-28029, Spain.
authors.forename: Jose A
authors.initials: JA
authors.lastname: Palacios
authors.forename: Daniel
authors.initials: D
authors.lastname: Herranz
authors.forename: Maria Luigia
authors.initials: ML
authors.lastname: De Bonis
authors.forename: Susana
authors.initials: S
authors.lastname: Velasco
authors.forename: Manuel
authors.initials: M
authors.lastname: Serrano
authors.forename: Maria A
authors.initials: MA
authors.lastname: Blasco
mesh_terms: D000107:Acetylation; D000375:Aging / Q000235:genetics; D000818:Animals; D002503:Centromere / Q000235:genetics / Q000378:metabolism; D002873:Chromosome Fragility / Q000235:genetics; D002875:Chromosomes / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics; D004622:Embryo, Mammalian / Q000166:cytology; D005347:Fibroblasts / Q000378:metabolism; D015870:Gene Expression / Q000235:genetics; D006655:Histone Deacetylases / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011485:Protein Binding / Q000235:genetics; D012313:RNA / Q000235:genetics; D011995:Recombination, Genetic / Q000235:genetics*; D056564:Sirtuin 1 / Q000235:genetics*; D012854:Sister Chromatid Exchange / Q000235:genetics; D019098:Telomerase / Q000235:genetics / Q000378:metabolism; D016615:Telomere / Q000235:genetics / Q000378:metabolism*
chemical_list: D006657:Histones; C422952:telomerase RNA; D012313:RNA; D019098:Telomerase; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; D006655:Histone Deacetylases