Genomic instability and aging-like phenotype in the absence of mammalian SIRT6
Genomic instability and aging-like phenotype in the absence of mammalian SIRT6
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DOI：
10.1016/j.cell.2005.11.044
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发表时间：
2006-01-27
期刊：
影响因子：
64.5
通讯作者：
Alt, FW
中科院分区：
文献类型：
--
作者：
Mostoslavsky, R;Chua, KF;Alt, FW
Sir2 组蛋白脱乙酰酶充当染色质沉默子，调节芽殖酵母中的重组、基因组稳定性和衰老。已鉴定出 7 个哺乳动物 Sir2 同源物（SIRT1-SIRT7），并且推测其中一些可能具有与 Sir2 相似的功能。在这里，我们证明 SIRT6 是一种核染色质相关蛋白，可促进小鼠细胞对 DNA 损伤的抵抗并抑制基因组不稳定性，并与碱基切除修复 (BER) 中的作用相关。 SIRT6缺陷的小鼠体型较小，在2-3周龄时会出现异常，包括严重的淋巴细胞减少、皮下脂肪减少、脊柱前凸和严重的代谢缺陷，最终在约4周时死亡。我们得出的结论是，SIRT6 的功能之一是促进正常的 DNA 修复，而 SIRT6 的缺失会导致小鼠出现与衰老相关的退行性过程重叠的异常。
The Sir2 histone deacetylase functions as a chromatin silencer to regulate recombination, genomic stability, and aging in budding yeast. Seven mammalian Sir2 homologs have been identified (SIRT1-SIRT7), and it has been speculated that some may have similar functions to Sir2. Here, we demonstrate that SIRT6 is a nuclear, chromatin-associated protein that promotes resistance to DNA damage and suppresses genomic instability in mouse cells, in association with a role in base excision repair (BER). SIRT6-deficient mice are small and at 2-3 weeks of age develop abnormalities that include profound lymphopenia, loss of subcutaneous fat, lordokyphosis, and severe metabolic defects, eventually dying at about 4 weeks. We conclude that one function of SIRT6 is to promote normal DNA repair, and that SIRT6 loss leads to abnormalities in mice that overlap with aging-associated degenerative processes.