WSTF regulates the function of H2A.X via a novel tyrosine kinase activity

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.