ATM and SIRT6/SNF2H Mediate Transient H2AX Stabilization When DSBs Form by Blocking HUWE1 to Allow Efficient γH2AX Foci Formation

Yuko Atsumi, Yusuke Minakawa, Masaya Ono, Sachiko Dobashi, Keitaro Shinohe, Akira Shinohara, Shunichi Takeda, Masatoshi Takagi, Nobuhiko Takamatsu, Hitoshi Nakagama, Hirobumi Teraoka, Ken-ichi Yoshioka
2015 Cell Reports  
Graphical Abstract Highlights d H2AX is degraded via poly-ubiquitination mediated by HUWE1 d H2AX is transiently stabilized upon DSB formation to efficiently form gH2AX foci d H2AX stabilization is mediated by ATM, SIRT6, and SNF2H SUMMARY In response to DNA double-strand breaks (DSBs), H2AX is rapidly phosphorylated at Ser139 to promote DSB repair. Here we show that H2AX is rapidly stabilized in response to DSBs to efficiently generate gH2AX foci. This mechanism operated even in quiescent
more » ... n in quiescent cells that barely expressed H2AX. H2AX stabilization resulted from the inhibition of proteasomemediated degradation. Synthesized H2AX ordinarily underwent degradation through poly-ubiquitination mediated by the E3 ligase HUWE1; however, H2AX ubiquitination was transiently halted upon DSB formation. Such rapid H2AX stabilization by DSBs was associated with chromatin incorporation of H2AX and halting of its poly-ubiquitination mediated by the ATM kinase, the sirtuin protein SIRT6, and the chromatin remodeler SNF2H. H2AX Ser139, the ATM phosphorylation site, was essential for H2AX stabilization upon DSB formation. Our results reveal a pathway controlled by ATM, SIRT6, and SNF2H to block HUWE1, which stabilizes H2AX and induces its incorporation into chromatin only when cells are damaged.
doi:10.1016/j.celrep.2015.11.054 pmid:26711340 fatcat:yxuaja2nbfe7pmalmd5uowzvtq