Abstract
The human enzyme histone acetyltransferase binding to ORC1 (HBO1) regulates DNA replication, cell proliferation, and development. HBO1 is part of a multiprotein histone acetyltransferase (HAT) complex that also contains inhibitor of growth family member (ING) 4/5, MYST/Esa1-associated factor (MEAF) 6, and the scaffolding proteins Jade family PHD finger (JADE) 1/2/3 or bromodomain and PHD finger-containing protein (BRPF) 2/3 to acetylate histone H4 H4K5/8/12 or H3K14, respectively. Within this four-protein complex, JADE1 determines histone H4 substrate specificity of the HBO1-HAT complex. However, the mechanism by which JADE1 controls the H4-specific acetyltransferase activity of HBO1 is unknown. Here we used recombinant proteins in vitro to dissect the specific regions and activities of HBO1 and JADE1 that mediate histone H3-H4 acetylation via the HBO1-HAT domain. We found that JADE1 increases the catalytic efficiency of HBO1 acetylation of an H3-H4 substrate by about 5-fold through an N-terminal, 21-residue HBO1- and histone-binding domain and a nearby second histone core-binding domain. We also demonstrate that HBO1 contains an N-terminal histone-binding domain (HBD) that makes additional contacts with H3-H4 independent of JADE1 interactions with histones and that the HBO1 HBD does not significantly contribute to HBO1's overall HAT activity. Experiments with JADE1 deletions in vivo recapitulated these in vitro interactions and their roles in HBO1 histone acetylation activity. Together, these results indicate that the N-terminal region of JADE1 functions as a platform that brings together the catalytic HBO1 subunit with its cognate H3-H4 substrate for histone acetylation.
Highlights
The human enzyme histone acetyltransferase binding to ORC1 (HBO1) regulates DNA replication, cell proliferation, and development
We found that JADE1 contains specific HBO1 and histone binding regions that serve to increase the catalytic efficiency of HBO1 acetylation of histone H4
It was previously demonstrated that an N-terminal region of JADE1 between residues 90 –199 participated in HBO1 catalytic activity (15)
Summary
Dept. of Biochemistry and Biophysics, Abramson Family Cancer Research Institute, Perelman School of Medicine at the University of Pennsylvania, 421 Curie Blvd., Philadelphia, PA 19104. Human HBO1 ( referenced as KAT7 or MYST2), a member of the MYST family, regulates DNA replication (13, 14), cell proliferation, and development (15) Consistent with their role in gene expression, HBO1–HAT complexes are localized at transcription start sites and coding regions of active genes in the genome (16) and are responsible for the majority of H4 (14, 17, 18) and H3K14 (19, 20) acetylation. ING can link its aforementioned tumor suppressor function with chromatin binding, transcriptional activity, and cellular proliferation by nucleating the complex recruitment process (15, 24, 25). This is further substantiated by the activity of JADE1 spliced variants. The implications of these studies for the differential regulation of HBO1 by JADE1 and BRPF1 paralogs are discussed
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