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Chemical Synthesis of Phosphorylated Histone H2A at Tyr57 Reveals Insight into the Inhibition Mode of the SAGA Deubiquitinating Module
Author(s) -
Jbara Muhammad,
Maity Suman Kumar,
Morgan Michael,
Wolberger Cynthia,
Brik Ashraf
Publication year - 2016
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201600638
Subject(s) - histone h2b , histone acetyltransferase , deubiquitinating enzyme , histone , acetylation , phosphorylation , coactivator , histone methyltransferase , histone acetyltransferases , microbiology and biotechnology , demethylation , acetyltransferase , chemistry , ubiquitin , histone h2a , biology , biochemistry , transcription factor , dna methylation , dna , gene , gene expression
Monoubiquitination of histone H2B plays a central role in transcription activation and is required for downstream histone‐methylation events. Deubiquitination of H2B by the Spt‐Ada‐Gcn5 acetyltransferase (SAGA) coactivator complex is regulated by a recently discovered histone mark, phosphorylated H2AY57 (H2AY57p), which inhibits deubiquitination of H2B by the SAGA complex as well as restricting demethylation of H3 and increasing its acetylation. Evidence for the effect of H2AY57p, however, was indirect and was investigated in vivo by monitoring the effects of chemical inhibition of Tyr kinase CK2 or by mutating the phosphorylation site. We applied the total chemical synthesis of proteins to prepare H2AY57p efficiently and study the molecular details of this regulation. This analogue, together with semisynthetically prepared ubiquitinated H2B, enabled us to provide direct evidence for the cross‐talk between those two marks and the inhibition of SAGA activity by H2AY57p.