PRMT5-Dependent Methylation of the TIP60 Coactivator RUVBL1 Is a Key Regulator of Homologous Recombination.
PRMT5-Dependent Methylation of the TIP60 Coactivator RUVBL1 Is a Key Regulator of Homologous Recombination.
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DOI：
10.1016/j.molcel.2017.01.019
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发表时间：
2017-03-02
期刊：
影响因子：
16
通讯作者：
Davies CC
中科院分区：
文献类型：
--
作者：
Clarke TL;Sanchez-Bailon MP;Chiang K;Reynolds JJ;Herrero-Ruiz J;Bandeiras TM;Matias PM;Maslen SL;Skehel JM;Stewart GS;Davies CC
蛋白质翻译后修饰在DNA修复调控中起着重要作用；然而，精氨酸甲基化在这一过程中的作用尚不清楚。在这里，我们发现精氨酸甲基转移酶PRMT5是同源重组（HR）介导的双链断裂（DSB）修复的关键调节因子，这是通过其甲基化RUVBL1的能力介导的，RUVBL1是TIP60复合体的辅助因子。我们发现PRMT5靶向RUVBL1在R205位点的甲基化，这促进了依赖tip60的53BP1从DNA断裂中动员，促进了HR。从机制上讲，我们证明prmt5导向的RUVBL1甲基化是TIP60乙酰转移酶活性的关键，促进组蛋白H4K16乙酰化，从而促进53BP1从dsb中位移。有趣的是，RUVBL1甲基化并不影响TIP60促进ATM激活的能力。综上所述，我们的研究结果揭示了prmt5介导的精氨酸甲基化在DSB修复途径选择中的重要性，通过其调节53BP1定位的乙酰化依赖控制的能力。PRMT5是同源重组介导的双链断裂修复的调节因子，PRMT5在R205位点甲基化RUVBL1；调节tip60介导的组蛋白乙酰化RUVBL1甲基化缺失导致53BP1保留在断裂端精氨酸甲基化与组蛋白乙酰化串串调节修复途径选择Clarke等人表明，通过促进tip60介导的组蛋白H4K16乙酰化，精氨酸甲基化转移酶PRMT5对RUVBL1的甲基化是同源重组介导的双链断裂修复所必需的。PRMT5活性丧失和RUVBL1甲基化缺陷导致53BP1保留，对DNA损伤剂的敏感性增加，以及基因组不稳定。
Protein post-translation modification plays an important role in regulating DNA repair; however, the role of arginine methylation in this process is poorly understood. Here we identify the arginine methyltransferase PRMT5 as a key regulator of homologous recombination (HR)-mediated double-strand break (DSB) repair, which is mediated through its ability to methylate RUVBL1, a cofactor of the TIP60 complex. We show that PRMT5 targets RUVBL1 for methylation at position R205, which facilitates TIP60-dependent mobilization of 53BP1 from DNA breaks, promoting HR. Mechanistically, we demonstrate that PRMT5-directed methylation of RUVBL1 is critically required for the acetyltransferase activity of TIP60, promoting histone H4K16 acetylation, which facilities 53BP1 displacement from DSBs. Interestingly, RUVBL1 methylation did not affect the ability of TIP60 to facilitate ATM activation. Taken together, our findings reveal the importance of PRMT5-mediated arginine methylation during DSB repair pathway choice through its ability to regulate acetylation-dependent control of 53BP1 localization. PRMT5 is a regulator of homologous recombination-mediated double-strand break repair PRMT5 methylates RUVBL1 at R205, regulating TIP60-mediated histone acetylation Loss of RUVBL1 methylation leads to 53BP1 retention at break ends Arginine methylation crosstalks with histone acetylation to regulate repair pathway choice Clarke et al. show that methylation of RUVBL1 by the arginine methyltransferase PRMT5 is required for homologous recombination-mediated double-strand break repair by promoting TIP60-mediated histone H4K16 acetylation. Loss of PRMT5 activity and defective RUVBL1 methylation leads to 53BP1 retention, increased sensitivity to DNA damaging agents, and genome instability.