Journal article
Mechanism of Histone H3K4me3 Recognition by the Plant Homeodomain of Inhibitor of Growth 3
The Journal of biological chemistry, Vol.291(35), pp.18326-18341
08/26/2016
Handle:
https://hdl.handle.net/2376/112565
PMCID: PMC5000080
PMID: 27281824
Abstract
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 μ
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.
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Details
- Title
- Mechanism of Histone H3K4me3 Recognition by the Plant Homeodomain of Inhibitor of Growth 3
- Creators
- Sophia Kim - From theSenthil Natesan - From theGabriel Cornilescu - theSamuel Carlson - From theMarco Tonelli - theUrszula L McClurg - theOlivier Binda - theCraig N Robson - theJohn L Markley - theStefan Balaz - From theKaren C Glass - From the
- Publication Details
- The Journal of biological chemistry, Vol.291(35), pp.18326-18341
- Academic Unit
- Pharmaceutical Sciences, Department of
- Publisher
- American Society for Biochemistry and Molecular Biology; 11200 Rockville Pike, Suite 302, Rockville, MD 20852-3110, U.S.A
- Grant note
- 2013MaySP005 / Breast Cancer Campaign JG/ML/0414 / Joint Research Executive Scientific Committee DMB-8415048; OIA-9977486; BIR-9214394 / National Science Foundation PG09–23 / Prostate Cancer UK 1R15GM104865; P41GM103399; S10RR02781; S10RR08438; S10RR023438; S10RR025062; S10RR029220 / National Institutes of Health Cys-27826/A15994 / Cancer Research UK
- Identifiers
- 99900547667301842
- Language
- English
- Resource Type
- Journal article