Conserved Molecular Interactions within the HBO1 Acetyltransferase Complexes Regulate Cell Proliferation

Abstract

Acetyltransferase complexes of the MYST family with distinct substrate specificities and functions maintain a conserved association with different ING tumor suppressor proteins. ING complexes containing the HBO1 acetylase are a major source of histone H3 and H4 acetylation in vivo and play critical roles in gene regulation and DNA replication. Here, our molecular dissection of HBO1/ING complexes unravels the protein domains required for their assembly and function. Multiple PHD finger domains present in different subunits bind the histone H3 N-terminal tail with a distinct specificity toward lysine 4 methylation status. We show that natively regulated association of the ING4/5 PHD domain with HBO1-JADE determines the growth inhibitory function of the complex, linked to its tumor suppressor activity. Functional genomic analyses indicate that the p53 pathway is a main target of the complex, at least in part through direct transcription regulation at the initiation site of p21/CDKN1A. These results demonstrate the importance of ING association with MYST acetyltransferases in controlling cell proliferation, a regulated link that accounts for the reported tumor suppressor activities of these complexes.

SUPPLEMENTAL MATERIAL

Supplemental material for this article may be found at http://dx.doi.org/10.1128/MCB.06455-11.

ACKNOWLEDGMENTS

We are grateful to Or Gozani for the biotinylated histone peptides, Song Tan for recombinant HBO1, JADE1, and ING4 vectors and help in the early stages of this study, Mitch Smith for recombinant HBO1 vectors, and Maria Panchenko for JADE1S vectors.

This work was supported by grants from the Canadian Institutes of Health Research (CIHR) to J.C. (MOP-64289), the Canadian Cancer Society Research Institute to X.-J.Y., and the National Institutes of Health to T.G.K. N.A. held a CIHR/Institute of Aging fellowship, M.-E.L. held a National Science and Engineering Research Council Ph.D. studentship, K.C.G. holds an American Heart Association award, and Y.D. held a CIHR/Canada Graduate Scholarship. J.C. is a Canada Research Chair.