Histone chaperone Anp32e removes H2A.Z from DNA double-strand breaks and promotes nucleosome reorganization and DNA repair
Histone chaperone Anp32e removes H2A.Z from DNA double-strand breaks and promotes nucleosome reorganization and DNA repair
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DOI：
10.1073/pnas.1504868112
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发表时间：
2015-06-16
影响因子：
11.1
通讯作者：
Price, Brendan D.
中科院分区：
文献类型：
--
作者：
Gursoy-Yuzugullu, Ozge;Ayrapetov, Marina K.;Price, Brendan D.
DNA双链断裂（DSB）的修复需要开放的、柔性的染色质结构域。NuA 4-Tip 60复合物通过将组蛋白H2A.Z交换到核小体上并促进组蛋白H4的乙酰化来产生这些灵活的染色质结构。在这里，我们证明了在DSB核小体上H2A.Z的积累是短暂的，并且DSB修复需要快速驱逐H2A.Z。Anp 32 e是一种与H2A.Z的C-末端对接结构域相互作用的H2A.Z分子伴侣，其被快速募集到DSB。Anp 32 e的功能是从核小体中去除H2A.Z，使H2A.Z水平在DNA损伤后10分钟内恢复到基础水平。此外，通过Anp 32 e去除H2A.Z破坏了组蛋白H4尾部与核小体表面之间的抑制性相互作用，促进了DNA损伤后组蛋白H4的乙酰化增加。当Anp 32 e去除H2A.Z被阻断时，DSB处的核小体保留较高水平的H2A.Z，并呈现更稳定的低乙酰化构象。此外，Anp 32 e的缺失导致CtIP依赖性末端切除增加、单链DNA积累以及通过替代非同源末端连接途径的修复增加。因此，H2A.Z交换到染色质上并随后被Anp 32 e快速去除对于创建开放的乙酰化核小体结构和通过CtIP控制末端切除是至关重要的。Anp 32 e对H2A.Z交换和去除的动态调节揭示了核小体表面和核小体动力学在DSB修复过程中处理受损染色质模板的重要性。
The repair of DNA double-strand breaks (DSBs) requires open, flexible chromatin domains. The NuA4-Tip60 complex creates these flexible chromatin structures by exchanging histone H2A.Z onto nucleosomes and promoting acetylation of histone H4. Here, we demonstrate that the accumulation of H2A.Z on nucleosomes at DSBs is transient, and that rapid eviction of H2A.Z is required for DSB repair. Anp32e, an H2A.Z chaperone that interacts with the C-terminal docking domain of H2A.Z, is rapidly recruited to DSBs. Anp32e functions to remove H2A.Z from nucleosomes, so that H2A.Z levels return to basal within 10 min of DNA damage. Further, H2A.Z removal by Anp32e disrupts inhibitory interactions between the histone H4 tail and the nucleosome surface, facilitating increased acetylation of histone H4 following DNA damage. When H2A.Z removal by Anp32e is blocked, nucleosomes at DSBs retain elevated levels of H2A.Z, and assume a more stable, hypoacetylated conformation. Further, loss of Anp32e leads to increased CtIP-dependent end resection, accumulation of single-stranded DNA, and an increase in repair by the alternative non-homologous end joining pathway. Exchange of H2A.Z onto the chromatin and subsequent rapid removal by Anp32e are therefore critical for creating open, acetylated nucleosome structures and for controlling end resection by CtIP. Dynamic modulation of H2A.Z exchange and removal by Anp32e reveals the importance of the nucleosome surface and nucleosome dynamics in processing the damaged chromatin template during DSB repair.