1. Conserved molecular interactions within the HBO1 acetyltransferase complexes regulate cell proliferation.
- Author
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Avvakumov N, Lalonde ME, Saksouk N, Paquet E, Glass KC, Landry AJ, Doyon Y, Cayrou C, Robitaille GA, Richard DE, Yang XJ, Kutateladze TG, and Côté J
- Subjects
- Cell Line, Histone Acetyltransferases chemistry, Histones chemistry, Histones metabolism, Humans, Protein Structure, Tertiary, Tumor Suppressor Proteins chemistry, Tumor Suppressor Proteins metabolism, p21-Activated Kinases chemistry, p21-Activated Kinases metabolism, Cell Proliferation, Histone Acetyltransferases metabolism
- 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.
- Published
- 2012
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