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J Mol Biol. 2019 May 31;431(12):2298-2319. doi: 10.1016/j.jmb.2019.04.018. Epub 2019 Apr 24.

The Tumor Suppressor ING5 Is a Dimeric, Bivalent Recognition Molecule of the Histone H3K4me3 Mark.

Author information

1
CIC bioGUNE, Parque Tecnológico de Bizkaia, 48160 Derio, Spain.
2
Instituto de Investigaciones Biomédicas "Alberto Sols", CSIC-UAM, 28029 Madrid, Spain.
3
Institute for Research in Biomedicine, 08028 Barcelona, Spain.
4
CIC bioGUNE, Parque Tecnológico de Bizkaia, 48160 Derio, Spain; Department of Surgery and Cancer, Imperial College London, London, W12 0NN, UK.
5
CIC bioGUNE, Parque Tecnológico de Bizkaia, 48160 Derio, Spain; IKERBASQUE, Basque Foundation for Science, 48011 Bilbao, Spain. Electronic address: fblanco@cicbiogune.es.

Abstract

The INhibitor of Growth (ING) family of tumor suppressors regulates the transcriptional state of chromatin by recruiting remodeling complexes to sites with histone H3 trimethylated at lysine 4 (H3K4me3). This modification is recognized by the plant homeodomain (PHD) present at the C-terminus of the five ING proteins. ING5 facilitates histone H3 acetylation by the HBO1 complex, and also H4 acetylation by the MOZ/MORF complex. We show that ING5 forms homodimers through its N-terminal domain, which folds independently into an elongated coiled-coil structure. The central region of ING5, which contains the nuclear localization sequence, is flexible and disordered, but it binds dsDNA with micromolar affinity. NMR analysis of the full-length protein reveals that the two PHD fingers of the dimer are chemically equivalent and independent of the rest of the molecule, and they bind H3K4me3 in the same way as the isolated PHD. We have observed that ING5 can form heterodimers with the highly homologous ING4, and that two of three primary tumor-associated mutants in the N-terminal domain strongly destabilize the coiled-coil structure. They also affect cell proliferation and cell cycle phase distribution, suggesting a driver role in cancer progression.

KEYWORDS:

ING5; NMR; SAXS; chromatin; crystallography

PMID:
31026448
DOI:
10.1016/j.jmb.2019.04.018
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