Histone H3 K56 hyperacetylation perturbs replisomes and causes DNA damage
Histone H3 K56 hyperacetylation perturbs replisomes and causes DNA damage
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DOI：
10.1534/genetics.108.088914
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发表时间：
2008-08-01
期刊：
影响因子：
3.3
通讯作者：
Boeke, Jef D.
中科院分区：
文献类型：
--
作者：
Celic, Ivana;Verreault, Alain;Boeke, Jef D.
组蛋白H3 K56的去乙酰化，由沉默调节蛋白Hst 3 p和Hst 4p调节，对于维持基因组稳定性至关重要。然而，H3 K56去乙酰化m-c的生理后果知之甚少。在这里，我们表明缺乏Hst 3 p和Hst 4p的细胞，其中H3 K56是组成性的，超乙酰化的，表现出自发DNA损伤的标志，例如检查点激酶Rad 53 p的激活和DNA损伤诱导基因的上调。一致地，hst 3-hst 4细胞显示与突变的合成致死性相互作用，所述突变削弱参与DNA复制和DNA双链断裂（DSB）修复的基因。在大多数情况下，合成致死性取决于H3 K56的超乙酰化，因为它可以通过K56突变为精氨酸来抑制，这模拟了非乙酰化状态。我们还表明，hst 3和hst 4表型可以被PCNA钳加载器大亚基Rfclp的过表达和交替钳加载器CTF 18、RAD 24和ELGI的失活所抑制。CTF 4编码参与姐妹染色单体凝聚的复制体组分，CTF 4的缺失也抑制hst 3和hst 4表型。遗传分析表明，CTF 4是K56乙酰化途径的一部分，其会聚并调节复制体功能。该途径代表了维持基因组稳定性的重要机制，并且依赖于Hst 3 p和Hst 4p对H3 K56乙酰化的适当调节。我们的数据还表明，Rfclp和其他RFC复合物之间存在不稳定的平衡，并且RFC的非复制形式对具有全基因组和组成性H3 K56超乙酰化的细胞是非常有害的。
Deacetylation of histone H3 K56, regulated by the sirtuins Hst3p and Hst4p, is critical for maintenance of, genomic stability. However, the physiological consequences of a hick, of H3 K56 deacetylation m-c poorly understood. Here we show that cells lacking Hst3p) and Hst4p, in which H3 K56 is constitutively, hyperacetylated, exhibit hallmarks of spontaneous DNA damage, such is activation of the checkpoint kinase Rad53p and upregulation of DNA-damage inducible genes. Consistently, hst3 hst4 cells display synthetic lethality interactions with mutations that cripple genes involved in DNA replication and DNA double-strand break (DSB) repair. In most cases, synthetic lethality depends upon hyperacetylation of H3 K56 because it can he suppressed by mutation of K56 to arginine, which mimics the nonacetylated state. We also show that hst3 hst4 phenotypes can he suppressed by overexpression of the PCNA clamp loader large subunit, Rfclp, and by inactivation of, the alternative-clamp loaders CTF18, RAD24, and ELGI. Loss of, CTF4, encoding a replisome component involved in sister chromatid cohesion, also suppresses hst3 hst4 phenotypes. Genetic analysis suggests that CTF4 is a part of the K56 acetylation pathway that converges on and modulates replisomes function. This pahtway represents an important mechanism for maintenance of genomic stability mid depends upon proper regulation of H3 K56 acetylation by Hst3p and Hst4p. Our data also suggest the existence of a precarious balance between Rfclp and the other RFC complexes and that the nonreplicative forms of RFC are strongly deleterious to cells that have genomewide and constitutive H3 K56 hyperacetylation.