The sirtuins Hst3 and Hst4p preserve genome integrity by controlling histone H3 lysine 56 deacetylation
The sirtuins Hst3 and Hst4p preserve genome integrity by controlling histone H3 lysine 56 deacetylation
复制标题
DOI：
10.1016/j.cub.2006.06.023
复制
发表时间：
2006-07-11
期刊：
影响因子：
9.2
通讯作者：
Verreault, Alain
中科院分区：
文献类型：
--
作者：
Celic, Ivana;Masumoto, Hiroshi;Verreault, Alain
背景资料：组蛋白H3赖氨酸56（K56 Ac）的乙酰化在新合成的H3中通过S期时短暂发生，并在G2中被去除。然而，K56 Ac的生理作用和效应：营业额是unknow.Results：sirtuins Hst 3 p，并在较小程度上，Hst 4p维持低水平的K56 Ac的S期以外。在hst 3和hst 4突变体中，K56超乙酰化接近100%。对应于Sir 2 p的烟酰胺结合口袋的残基对于Hst 3 p功能是必需的，并且烟酰胺在体内抑制H3 K56脱乙酰化。在S期之前Hst 3/Hst 4p的快速失活使K56 Ac在G2中升高至50%，表明K56-乙酰化核小体在复制期间在全基因组范围内组装。Hst 3 p在G1或G2中的诱导表达触发成熟染色质的脱乙酰化。缺乏Hst 3/Hst 4p的细胞表现出许多表型：自发性DNA损伤、染色体丢失、热敏感性和对遗传毒性剂的急性敏感性。这些表型可通过组蛋白H3 K56突变为不可乙酰化的残基或在缺乏组蛋白伴侣Asf 1的细胞中K56 Ac的缺失而被抑制。结论：我们的结果强调了Hst 3/Hst 4p在控制组蛋白H3 K56 Ac从而维持染色体完整性方面的关键重要性。
Background: Acetylation of histone H3 lysine 56 (K56Ac) occurs transiently in newly synthesized H3 during passage through S phase and is removed in G2. However, the physiologic roles and effectors of K56Ac: turnover are unknown.Results: The sirtuins Hst3p and, to a lesser extent, Hst4p maintain low levels of K56Ac outside of S phase. In hst3 hst4 mutants, K56 hyperacetylation nears 100%. Residues corresponding to the nicotinamide binding pocket of Sir2p are essential for Hst3p function, and H3 K56 deacetylation is inhibited by nicotinamide in vivo. Rapid inactivation of Hst3/Hst4p prior to S phase elevates K56Ac to 50% in G2, suggesting that K56-acetylated nucleosomes are assembled genome-wide during replication. Inducible expression of Hst3p in G1 or G2 triggers deacetylation of mature chromatin. Cells lacking Hst3/Hst4p exhibit many phenotypes: spontaneous DNA damage, chromosome loss, thermosensitivity, and acute sensitivity to genotoxic agents. These phenotypes are suppressed by mutation of histone H3 K56 into a nonacetylatable residue or by loss of K56Ac in cells lacking the histone chaperone Asf1.Conclusions: Our results underscore the critical importance of Hst3/Hst4p in controlling histone H3 K56Ac and thereby maintaining chromosome integrity.