SIRT1 contributes to telomere maintenance and augments global homologous recombination

Author:

Palacios Jose A.1,Herranz Daniel1,De Bonis Maria Luigia12,Velasco Susana1,Serrano Manuel1,Blasco Maria A.1

Affiliation:

1. Telomeres and Telomerase Group and Tumor Suppression Group, Molecular Oncology Program, Spanish National Cancer Centre, Madrid E-28029, Spain

2. Istituto di Ricovero e Cura a Carattere Scientifico, Oncology Reference Center of Basilicata, Rionero in Vulture (PZ) 85028, Italy

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.

Publisher

Rockefeller University Press

Subject

Cell Biology

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