McCord Ronald A, Michishita Eriko, Hong Tao, Berber Elisabeth, Boxer Lisa D, Kusumoto Rika, Guan Shenheng, Shi Xiaobing, Gozani Or, Burlingame Alma L, Bohr Vilhelm A, Chua Katrin F
Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
Aging (Albany NY). 2009 Jan 15;1(1):109-21. doi: 10.18632/aging.100011.
The Sir2 chromatin regulatory factor links maintenance of genomic stability to life span extension in yeast. The mammalian Sir2 family member SIRT6 has been proposed to have analogous functions, because SIRT6-deficiency leads to shortened life span and an aging-like degenerative phenotype in mice, and SIRT6 knockout cells exhibit genomic instability and DNA damage hypersensitivity. However, the molecular mechanisms underlying these defects are not fully understood. Here, we show that SIRT6 forms a macromolecular complex with the DNA double-strand break (DSB) repair factor DNA-PK (DNA-dependent protein kinase) and promotes DNA DSB repair. In response to DSBs, SIRT6 associates dynamically with chromatin and is necessary for an acute decrease in global cellular acetylation levels on histone H3 Lysine 9. Moreover, SIRT6 is required for mobilization of the DNA-PK catalytic subunit (DNA-PKcs) to chromatin in response to DNA damage and stabilizes DNA-PKcs at chromatin adjacent to an induced site-specific DSB. Abrogation of these SIRT6 activities leads to impaired resolution of DSBs. Together, these findings elucidate a mechanism whereby regulation of dynamic interaction of a DNA repair factor with chromatin impacts on the efficiency of repair, and establish a link between chromatin regulation, DNA repair, and a mammalian Sir2 factor.
Sir2染色质调节因子将基因组稳定性的维持与酵母寿命的延长联系起来。哺乳动物Sir2家族成员SIRT6被认为具有类似的功能，因为SIRT6缺陷会导致小鼠寿命缩短和出现类似衰老的退行性表型，并且SIRT6基因敲除细胞表现出基因组不稳定和对DNA损伤的超敏反应。然而，这些缺陷背后的分子机制尚未完全了解。在此，我们表明SIRT6与DNA双链断裂（DSB）修复因子DNA-PK（DNA依赖性蛋白激酶）形成大分子复合物，并促进DNA DSB修复。响应DSB时，SIRT6动态地与染色质结合，并且对于组蛋白H3赖氨酸9上整体细胞乙酰化水平的急剧下降是必需的。此外，响应DNA损伤时，SIRT6是将DNA-PK催化亚基（DNA-PKcs）动员到染色质所必需的，并使DNA-PKcs在诱导的位点特异性DSB附近的染色质处稳定。这些SIRT6活性的丧失导致DSB的修复受损。总之，这些发现阐明了一种机制，即DNA修复因子与染色质的动态相互作用的调节影响修复效率，并在染色质调节、DNA修复和哺乳动物Sir2因子之间建立了联系。
