DNA double-strand breaks promote methylation of histone H3 on lysine 9 and transient formation of repressive chromatin
DNA double-strand breaks promote methylation of histone H3 on lysine 9 and transient formation of repressive chromatin
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DOI：
10.1073/pnas.1403565111
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发表时间：
2014-06-24
影响因子：
11.1
通讯作者：
Price, Brendan D.
中科院分区：
文献类型：
--
作者：
Ayrapetov, Marina K.;Gursoy-Yuzugullu, Ozge;Price, Brendan D.
组蛋白修饰的动态变化对于调节DNA双链断裂（DSB）修复至关重要。DSB激活Tip 60乙酰转移酶需要Tip 60与赖氨酸9上甲基化的组蛋白H3（H3 K9 me 3）相互作用。然而，H3 K9甲基化在DSB修复过程中如何调节尚不清楚。在这里，我们证明了一个复杂的含有kap-1，HP 1，和H3 K9甲基转移酶suv 39 h1是快速加载到染色质在DSB。Suv 39 h1甲基化H3 K9，通过将HP 1的染色体结构域结合到新生的H3 K9 me 3上，促进额外的kap-1/HP 1/suv 39 h1的负载。该过程启动了kap-1/HP 1/suv 39 h 1加载和H3 K9甲基化的循环，其促进了H3 K9 me 3和kap-1/HP 1/suv 39 h 1复合物从DSB中扩散出数十个酶。H3 K9 me 3的这些结构域的功能是激活Tip 60乙酰转移酶，使Tip 60乙酰化共济失调毛细血管扩张突变（ATM）激酶和组蛋白H4。因此，缺乏suv 39 h1的细胞显示Tip 60和ATM的激活缺陷，DSB修复减少，放射敏感性增加。重要的是，激活的ATM快速磷酸化kap-1，导致抑制性kap-1/HP 1/suv 39 h1复合物从染色质中释放。因此，ATM激活充当负反馈循环，以去除DSB处的抑制性suv 39 h1复合物，这可能会限制DSB修复。因此，将kap-1/HP 1/suv 39 h 1募集至DSB提供了一种机制，用于瞬时增加缺乏H3 K9 me 3的开放染色质结构域中的H3 K9 me 3水平，从而促进这些区域中Tip 60和ATM的有效活化。此外，抑制性染色质的瞬时形成对于稳定受损的染色质和重塑染色质以产生用于DNA修复机制的有效模板可能是关键的。
Dynamic changes in histone modification are critical for regulating DNA double-strand break (DSB) repair. Activation of the Tip60 acetyltransferase by DSBs requires interaction of Tip60 with histone H3 methylated on lysine 9 (H3K9me3). However, how H3K9 methylation is regulated during DSB repair is not known. Here, we demonstrate that a complex containing kap-1, HP1, and the H3K9 methyltransferase suv39h1 is rapidly loaded onto the chromatin at DSBs. Suv39h1 methylates H3K9, facilitating loading of additional kap-1/HP1/suv39h1 through binding of HP1's chromodomain to the nascent H3K9me3. This process initiates cycles of kap-1/HP1/suv39h1 loading and H3K9 methylation that facilitate spreading of H3K9me3 and kap-1/HP1/suv39h1 complexes for tens of kilobases away from the DSB. These domains of H3K9me3 function to activate the Tip60 acetyltransferase, allowing Tip60 to acetylate both ataxia telangiectasia-mutated (ATM) kinase and histone H4. Consequently, cells lacking suv39h1 display defective activation of Tip60 and ATM, decreased DSB repair, and increased radiosensitivity. Importantly, activated ATM rapidly phosphorylates kap-1, leading to release of the repressive kap-1/HP1/suv39h1 complex from the chromatin. ATM activation therefore functions as a negative feedback loop to remove repressive suv39h1 complexes at DSBs, which may limit DSB repair. Recruitment of kap-1/HP1/suv39h1 to DSBs therefore provides a mechanism for transiently increasing the levels of H3K9me3 in open chromatin domains that lack H3K9me3 and thereby promoting efficient activation of Tip60 and ATM in these regions. Further, transient formation of repressive chromatin may be critical for stabilizing the damaged chromatin and for remodeling the chromatin to create an efficient template for the DNA repair machinery.