WSTF regulates the H2A.X DNA damage response via a novel tyrosine kinase activity.
WSTF regulates the H2A.X DNA damage response via a novel tyrosine kinase activity.
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DOI：
10.1038/nature07668
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发表时间：
2009-01-01
期刊：
影响因子：
64.8
通讯作者：
Allis, C. David
中科院分区：
文献类型：
--
作者：
Xiao, Andrew;Li, Haitao;Shechter, David;Ahn, Sung Hee;Fabrizio, Laura A.;Erdjument-Bromage, Hediye;Ishibe-Murakami, Satoko;Wang, Bin;Tempst, Paul;Hofmann, Kay;Patel, Dinshaw J.;Elledge, Stephen J.;Allis, C. David
DNA双链断裂对真核细胞提出了严峻的挑战。不能修复断裂导致基因组不稳定、致癌和细胞死亡。在DSB反应期间，哺乳动物染色质经历由H2A.X Ser 139磷酸化（γ-H2A.X）划分的重组。然而，γ-H2A.X磷酸化的调节及其在修复过程中染色质重塑中的确切作用仍不清楚。在这里，我们报告了一种新的调节机制介导的WSTF，WICH ATP依赖的染色质重塑复合物的一个组成部分。我们表明，WSTF具有内在的酪氨酸激酶活性，通过一个结构域，没有任何已知的激酶折叠序列同源性。我们发现，WSTF磷酸化H2A.X的Tyr 142，WSTF活性在调节DNA损伤反应的关键事件中起着重要作用。我们的工作揭示了一种新的机制，调节DNA损伤反应，并扩大了我们的知识域，含有内在酪氨酸激酶活性。
DNA double-stranded breaks present a serious challenge for eukaryotic cells. Inability to repair breaks leads to genomic instability, carcinogenesis, and cell death. During the DSB response, mammalian chromatin undergoes reorganization demarcated by H2A.X Ser139 phosphorylation (γ-H2A.X). However, the regulation of γ-H2A.X phosphorylation and its precise role in chromatin remodeling during the repair process remain unclear. Here, we report a novel regulatory mechanism mediated by WSTF, a component of the WICH ATP-dependent chromatin remodeling complex. We show that WSTF has intrinsic tyrosine kinase activity via a domain that shares no sequence homology to any known kinase fold. We show that WSTF phosphorylates Tyr142 of H2A.X and that WSTF activity plays an important role in regulating a number of events that are critical for the DNA damage response. Our work reveals a novel mechanism that regulates the DNA damage response and expands our knowledge of domains that contain intrinsic tyrosine kinase activity.
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