Phospho-dependent recruitment of the yeast NuA4 acetyltransferase complex by MRX at DNA breaks regulates RPA dynamics during resection
Phospho-dependent recruitment of the yeast NuA4 acetyltransferase complex by MRX at DNA breaks regulates RPA dynamics during resection
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DOI：
10.1073/pnas.1806513115
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发表时间：
2018-10-02
影响因子：
11.1
通讯作者：
Cote, Jacques
中科院分区：
文献类型：
--
作者：
Cheng, Xue;Jobin-Robitaille, Olivier;Cote, Jacques
KAT 5（Tip 60/Esa 1）组蛋白乙酰转移酶是NuA 4的一部分，NuA 4是一种从酵母到哺乳动物高度保守的大型多功能复合物，靶向H4和H2 A（X/Z）尾部的赖氨酸进行乙酰化。它对细胞活力至关重要，是基因表达、细胞增殖和干细胞更新的关键调节因子，也是基因组稳定性的重要因素。NuA 4复合物在DNA双链断裂（DSB）附近直接募集以促进修复，部分通过局部染色质修饰和在DNA损伤反应期间与53 BP 1相互作用。虽然NuA 4在病变出现后早期被检测到，但其确切的募集机制仍有待确定。在这里，我们报告了一个逐步招聘酵母NuA 4 DSB首先通过DNA损伤诱导的磷酸化依赖性的相互作用与Xrs 2亚基的Mre 11-Rad 50-Xrs 2（MRX）复合物结合到DNA末端。随后是NuA 4在断裂的每一侧沿着与ssDNA结合的复制蛋白A（RPA）的DNA切除依赖性扩散。最后，我们表明，NuA 4可以乙酰化RPA，并调节其与DNA结合的动力学，因此针对局部组蛋白和非组蛋白蛋白的赖氨酸乙酰化，以协调修复。
The KAT5 (Tip60/Esa1) histone acetyltransferase is part of NuA4, a large multifunctional complex highly conserved from yeast to mammals that targets lysines on H4 and H2A (X/Z) tails for acetylation. It is essential for cell viability, being a key regulator of gene expression, cell proliferation, and stem cell renewal and an important factor for genome stability. The NuA4 complex is directly recruited near DNA double-strand breaks (DSBs) to facilitate repair, in part through local chromatin modification and interplay with 53BP1 during the DNA damage response. While NuA4 is detected early after appearance of the lesion, its precise mechanism of recruitment remains to be defined. Here, we report a stepwise recruitment of yeast NuA4 to DSBs first by a DNA damage-induced phosphorylation-dependent interaction with the Xrs2 subunit of the Mre11-Rad50-Xrs2 (MRX) complex bound to DNA ends. This is followed by a DNA resection-dependent spreading of NuA4 on each side of the break along with the ssDNA-binding replication protein A (RPA). Finally, we show that NuA4 can acetylate RPA and regulate the dynamics of its binding to DNA, hence targeting locally both histone and nonhistone proteins for lysine acetylation to coordinate repair.