Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China.
2011 Collaborative Innovation Center of Tianjin for Medical Epigenetics, Tianjin Key Laboratory of Medical Epigenetics, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China.
Nat Commun. 2016 Jul 20;7:12235. doi: 10.1038/ncomms12235.
Although SIRT7 is a member of sirtuin family proteins that are described as NAD(+)-dependent class III histone deacetylases, the intrinsic enzymatic activity of this sirtuin protein remains to be investigated and the cellular function of SIRT7 remains to be explored. Here we report that SIRT7 is an NAD(+)-dependent histone desuccinylase. We show that SIRT7 is recruited to DNA double-strand breaks (DSBs) in a PARP1-dependent manner and catalyses desuccinylation of H3K122 therein, thereby promoting chromatin condensation and DSB repair. We demonstrate that depletion of SIRT7 impairs chromatin compaction during DNA-damage response and sensitizes cells to genotoxic stresses. Our study indicates SIRT7 is a histone desuccinylase, providing a molecular basis for the understanding of epigenetic regulation by this sirtuin protein. Our experiments reveal that SIRT7-catalysed H3K122 desuccinylation is critically implemented in DNA-damage response and cell survival, providing a mechanistic insight into the cellular function of SIRT7.
虽然 SIRT7 是 sirtuin 家族蛋白的成员，被描述为 NAD(+)依赖的 III 类组蛋白去乙酰化酶，但这种 sirtuin 蛋白的内在酶活性仍有待研究，SIRT7 的细胞功能仍有待探索。在这里，我们报告 SIRT7 是一种 NAD(+)依赖的组蛋白去琥珀酰基酶。我们表明，SIRT7 以依赖 PARP1 的方式被招募到 DNA 双链断裂 (DSB)，并催化其中的 H3K122 去琥珀酰化，从而促进染色质浓缩和 DSB 修复。我们证明，SIRT7 的耗竭会在 DNA 损伤反应过程中损害染色质的紧缩，并使细胞对遗传毒性应激敏感。我们的研究表明 SIRT7 是一种组蛋白去琥珀酰基酶，为理解这种 sirtuin 蛋白的表观遗传调控提供了分子基础。我们的实验表明，SIRT7 催化的 H3K122 去琥珀酰化在 DNA 损伤反应和细胞存活中至关重要，为 SIRT7 的细胞功能提供了机制上的见解。
