Telomeres and Telomerase Group, Spanish National Cancer Centre, Madrid E-28029, Spain.
J Cell Biol. 2010 Dec 27;191(7):1299-313. doi: 10.1083/jcb.201005160.
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.
酵母 Sir2 脱乙酰酶是沉默信息调节因子 (SIR) 复合物的组成部分，该复合物包含 Sir2/Sir3/Sir4。Sir2 通过 Rap1 招募到端粒，该复合物通过组蛋白脱乙酰化在端粒周围的 DNA 中扩散。然而，酵母 Sir2 的哺乳动物同源物 SIRT1 在端粒上的潜在功能不太清楚。我们研究了功能丧失（SIRT1 缺陷）和功能获得（SIRT1(super)）的小鼠模型。我们的结果表明，SIRT1 是体内端粒长度的正调节剂，并减弱与衰老相关的端粒缩短，这一效应依赖于端粒酶活性。使用染色质免疫沉淀测定，我们发现 SIRT1 在体内与端粒重复序列相互作用。此外，SIRT1 的过表达增加了整个基因组中的同源重组，包括端粒、着丝粒和染色体臂。这些发现将 SIRT1 与端粒生物学和全球 DNA 修复联系起来，并为 SIRT1 在保护 DNA 损伤和一些与年龄相关的病理方面的已知功能提供了新的机制解释。
