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
Laboratory of Chromatin Biology, The Rockefeller University, New York, New York 10065, USA.
Nature. 2009 Jan 1;457(7225):57-62. doi: 10.1038/nature07668. Epub 2008 Dec 17.
DNA double-stranded breaks present a serious challenge for eukaryotic cells. The inability to repair breaks leads to genomic instability, carcinogenesis and cell death. During the double-strand break response, mammalian chromatin undergoes reorganization demarcated by H2A.X Ser 139 phosphorylation (gamma-H2A.X). However, the regulation of gamma-H2A.X phosphorylation and its precise role in chromatin remodelling during the repair process remain unclear. Here we report a new regulatory mechanism mediated by WSTF (Williams-Beuren syndrome transcription factor, also known as BAZ1B)-a component of the WICH complex (WSTF-ISWI ATP-dependent chromatin-remodelling complex). We show that WSTF has intrinsic tyrosine kinase activity by means of a domain that shares no sequence homology to any known kinase fold. We show that WSTF phosphorylates Tyr 142 of H2A.X, and that WSTF activity has an important role in regulating several events that are critical for the DNA damage response. Our work demonstrates a new mechanism that regulates the DNA damage response and expands our knowledge of domains that contain intrinsic tyrosine kinase activity.
DNA双链断裂对真核细胞构成了严峻挑战。无法修复断裂会导致基因组不稳定、致癌作用和细胞死亡。在双链断裂反应过程中，哺乳动物染色质会发生以H2A.X丝氨酸139磷酸化（γ-H2A.X）为标志的重组。然而，γ-H2A.X磷酸化的调控及其在修复过程中对染色质重塑的确切作用仍不清楚。在此，我们报告一种由WSTF（威廉姆斯-博伦综合征转录因子，也称为BAZ1B）介导的新调控机制，WSTF是WICH复合物（WSTF-ISWI ATP依赖性染色质重塑复合物）的一个组成部分。我们发现WSTF通过一个与任何已知激酶结构域均无序列同源性的结构域具有内在酪氨酸激酶活性。我们表明WSTF使H2A.X的酪氨酸142磷酸化，并且WSTF活性在调节对DNA损伤反应至关重要的几个事件中起重要作用。我们的工作证明了一种调节DNA损伤反应的新机制，并扩展了我们对含有内在酪氨酸激酶活性结构域的认识。
