WSTF regulates the H2A.X DNA damage response via a novel tyrosine kinase activity.
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.
Xiao
Andrew
A
Laboratory of Chromatin Biology, The Rockefeller University, New York, New York 10065, USA.
Li
Haitao
H
Shechter
David
D
Ahn
Sung Hee
SH
Fabrizio
Laura A
LA
Erdjument-Bromage
Hediye
H
Ishibe-Murakami
Satoko
S
Wang
Bin
B
Tempst
Paul
P
Hofmann
Kay
K
Patel
Dinshaw J
DJ
Elledge
Stephen J
SJ
Allis
C David
CD
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
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