title: WSTF regulates the H2A.X DNA damage response via a novel tyrosine kinase activity.
abstract: 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.
authors.affiliation: Laboratory of Chromatin Biology, The Rockefeller University, New York, New York 10065, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Xiao
authors.forename: Haitao
authors.initials: H
authors.lastname: Li
authors.forename: David
authors.initials: D
authors.lastname: Shechter
authors.forename: Sung Hee
authors.initials: SH
authors.lastname: Ahn
authors.forename: Laura A
authors.initials: LA
authors.lastname: Fabrizio
authors.forename: Hediye
authors.initials: H
authors.lastname: Erdjument-Bromage
authors.forename: Satoko
authors.initials: S
authors.lastname: Ishibe-Murakami
authors.forename: Bin
authors.initials: B
authors.lastname: Wang
authors.forename: Paul
authors.initials: P
authors.lastname: Tempst
authors.forename: Kay
authors.initials: K
authors.lastname: Hofmann
authors.forename: Dinshaw J
authors.initials: DJ
authors.lastname: Patel
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Elledge
authors.forename: C David
authors.initials: CD
authors.lastname: Allis
mesh_terms: D000251:Adenosine Triphosphatases / Q000378:metabolism; D000818:Animals; D042002:Chromatin Assembly and Disassembly; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism; D004249:DNA Damage; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D041681:NIH 3T3 Cells; D009707:Nucleosomes / Q000378:metabolism; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D014157:Transcription Factors / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000092468:Bromodomain Containing Proteins
chemical_list: D000251:Adenosine Triphosphatases; D002868:Chromosomal Proteins, Non-Histone; D006657:Histones; D009707:Nucleosomes; D019000:Phosphotyrosine; D011505:Protein-Tyrosine Kinases; D014157:Transcription Factors; C116750:BAZ1B protein, human; D000092468:Bromodomain Containing Proteins; C485505:Baz1b protein, mouse; C468783:H2AX protein, human; C498725:Smarca5 protein, mouse