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Lookup NU author(s): Dr Urszula McClurg, Dr Olivier Binda, Professor Craig Robson
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
Aberrant access to genetic information disrupts cellular homeostasis and can lead to cancer development. One molecular mechanism that regulates access to genetic information includes recognition of histone modifications, which is carried out by protein modules that interact with chromatin and serve as landing pads for enzymatic activities that regulate gene expression. The ING3 tumor suppressor protein contains a plant homeodomain (PHD) that reads the epigenetic code via recognition of histone H3 tri-methylated at lysine 4 (H3K4me3), and this domain is lost or mutated in various human cancers. However, the molecular mechanisms targeting ING3 to histones and the role of this interaction in the cell remain elusive. Thus, we employed biochemical and structural biology approaches to investigate the interaction of the ING3 PHD finger (ING3(PHD)) with the active transcription mark H3K4me3. Our results demonstrate that association of the ING3(PHD) with H3K4me3 is in the sub-micromolar range (K-D ranging between 0.63 and 0.93 m) and is about 200-fold stronger than with the unmodified histone H3. NMR and computational studies revealed an aromatic cage composed of Tyr-362, Ser-369, and Trp-385 that accommodate the tri-methylated side chain of H3K4. Mutational analysis confirmed the critical importance of Tyr-362 and Trp-385 in mediating the ING3(PHD)-H3K4me3 interaction. Finally, the biological relevance of ING3(PHD)-H3K4me3 binding was demonstrated by the failure of ING3(PHD) mutant proteins to enhance ING3-mediated DNA damage-dependent cell death. Together, our results reveal the molecular mechanism of H3K4me3 selection by the ING3(PHD) and suggest that this interaction is important for mediating ING3 tumor suppressive activities.
Author(s): Kim S, Natesan S, Cornilescu G, Carlson S, Tonelli M, McClurg UL, Binda O, Robson CN, Markley JL, Balaz S, Glass KC
Publication type: Article
Publication status: Published
Journal: Journal of Biological Chemistry
Year: 2016
Volume: 291
Issue: 35
Pages: 18326-18341
Print publication date: 26/08/2016
Online publication date: 08/06/2016
Acceptance date: 02/04/2016
Date deposited: 25/10/2016
ISSN (print): 0021-9258
ISSN (electronic): 1083-351X
Publisher: American Society for Biochemistry and Molecular Biology, Inc
URL: http://dx.doi.org/10.1074/jbc.M115.690651
DOI: 10.1074/jbc.M115.690651
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