WSTF regulates the H2A.X DNA damage response via a novel tyrosine kinase

DNAdouble-strandedbreakspresentaseriouschallengeforeukaryoticcells.Theinabilitytorepairbreaksleadstogenomicinstability, carcinogenesis and cell death. During the double-strand break response, mammalian chromatin undergoesreorganization demarcated by H2A.X Ser139 phosphorylation (c-H2A.X). However, the regulation of c-H2A.Xphosphorylationanditspreciseroleinchromatinremodellingduringtherepairprocessremainunclear.Herewereportanewregulatory mechanism mediated by WSTF (Williams–Beuren syndrome transcription factor, also known as BAZ1B)—acomponentoftheWICHcomplex(WSTF–ISWIATP-dependentchromatin-remodellingcomplex).WeshowthatWSTFhasintrinsictyrosinekinaseactivitybymeansofadomainthatsharesnosequencehomologytoanyknownkinasefold.WeshowthatWSTFphosphorylatesTyr142ofH2A.X,andthatWSTFactivityhasanimportantroleinregulatingseveraleventsthatare critical for the DNA damage response. Our work demonstrates a new mechanism that regulates the DNA damageresponse and expands our knowledge of domains that contain intrinsic tyrosine kinase activity.