Histone H3K4me3 Binding Is Required for the DNA Repair and Apoptotic Activities of ING1 Tumor Suppressor

P. V. Peña, R. A. Hom, T. Hung, H. Lin, A. J. Kuo, R. P C Wong, O. M. Subach, K. S. Champagne, R. Zhao, Vladislav Verkhusha, G. Li, O. Gozani, T. G. Kutateladze

Research output: Contribution to journalArticle

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Abstract

Inhibitor of growth 1 (ING1) is implicated in oncogenesis, DNA damage repair, and apoptosis. Mutations within the ING1 gene and altered expression levels of ING1 are found in multiple human cancers. Here, we show that both DNA repair and apoptotic activities of ING1 require the interaction of the C-terminal plant homeodomain (PHD) finger with histone H3 trimethylated at Lys4 (H3K4me3). The ING1 PHD finger recognizes methylated H3K4 but not other histone modifications as revealed by the peptide microarrays. The molecular mechanism of the histone recognition is elucidated based on a 2.1 Å-resolution crystal structure of the PHD-H3K4me3 complex. The K4me3 occupies a deep hydrophobic pocket formed by the conserved Y212 and W235 residues that make cation-π contacts with the trimethylammonium group. Both aromatic residues are essential in the H3K4me3 recognition, as substitution of these residues with Ala disrupts the interaction. Unlike the wild-type ING1, the W235A mutant, overexpressed in the stable clones of melanoma cells or in HT1080 cells, was unable to stimulate DNA repair after UV irradiation or promote DNA-damage-induced apoptosis, indicating that H3K4me3 binding is necessary for these biological functions of ING1. Furthermore, N216S, V218I, and G221V mutations, found in human malignances, impair the ability of ING1 to associate with H3K4me3 or to induce nucleotide repair and cell death, linking the tumorigenic activity of ING1 with epigenetic regulation. Together, our findings reveal the critical role of the H3K4me3 interaction in mediating cellular responses to genotoxic stresses and offer new insight into the molecular mechanism underlying the tumor suppressive activity of ING1.

Original languageEnglish (US)
Pages (from-to)303-312
Number of pages10
JournalJournal of Molecular Biology
Volume380
Issue number2
DOIs
StatePublished - Jul 4 2008

Fingerprint

Growth Inhibitors
DNA Repair
Histones
Neoplasms
DNA Damage
Histone Code
Apoptosis
Plant Structures
Mutation
Epigenomics
Fingers
Cations
Melanoma
Carcinogenesis
Cell Death
Nucleotides
Clone Cells
Gene Expression

Keywords

  • cancer
  • histone
  • ING1
  • PHD finger
  • structure

ASJC Scopus subject areas

  • Virology

Cite this

Peña, P. V., Hom, R. A., Hung, T., Lin, H., Kuo, A. J., Wong, R. P. C., ... Kutateladze, T. G. (2008). Histone H3K4me3 Binding Is Required for the DNA Repair and Apoptotic Activities of ING1 Tumor Suppressor. Journal of Molecular Biology, 380(2), 303-312. https://doi.org/10.1016/j.jmb.2008.04.061

Histone H3K4me3 Binding Is Required for the DNA Repair and Apoptotic Activities of ING1 Tumor Suppressor. / Peña, P. V.; Hom, R. A.; Hung, T.; Lin, H.; Kuo, A. J.; Wong, R. P C; Subach, O. M.; Champagne, K. S.; Zhao, R.; Verkhusha, Vladislav; Li, G.; Gozani, O.; Kutateladze, T. G.

In: Journal of Molecular Biology, Vol. 380, No. 2, 04.07.2008, p. 303-312.

Research output: Contribution to journalArticle

Peña, PV, Hom, RA, Hung, T, Lin, H, Kuo, AJ, Wong, RPC, Subach, OM, Champagne, KS, Zhao, R, Verkhusha, V, Li, G, Gozani, O & Kutateladze, TG 2008, 'Histone H3K4me3 Binding Is Required for the DNA Repair and Apoptotic Activities of ING1 Tumor Suppressor', Journal of Molecular Biology, vol. 380, no. 2, pp. 303-312. https://doi.org/10.1016/j.jmb.2008.04.061
Peña, P. V. ; Hom, R. A. ; Hung, T. ; Lin, H. ; Kuo, A. J. ; Wong, R. P C ; Subach, O. M. ; Champagne, K. S. ; Zhao, R. ; Verkhusha, Vladislav ; Li, G. ; Gozani, O. ; Kutateladze, T. G. / Histone H3K4me3 Binding Is Required for the DNA Repair and Apoptotic Activities of ING1 Tumor Suppressor. In: Journal of Molecular Biology. 2008 ; Vol. 380, No. 2. pp. 303-312.
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abstract = "Inhibitor of growth 1 (ING1) is implicated in oncogenesis, DNA damage repair, and apoptosis. Mutations within the ING1 gene and altered expression levels of ING1 are found in multiple human cancers. Here, we show that both DNA repair and apoptotic activities of ING1 require the interaction of the C-terminal plant homeodomain (PHD) finger with histone H3 trimethylated at Lys4 (H3K4me3). The ING1 PHD finger recognizes methylated H3K4 but not other histone modifications as revealed by the peptide microarrays. The molecular mechanism of the histone recognition is elucidated based on a 2.1 {\AA}-resolution crystal structure of the PHD-H3K4me3 complex. The K4me3 occupies a deep hydrophobic pocket formed by the conserved Y212 and W235 residues that make cation-π contacts with the trimethylammonium group. Both aromatic residues are essential in the H3K4me3 recognition, as substitution of these residues with Ala disrupts the interaction. Unlike the wild-type ING1, the W235A mutant, overexpressed in the stable clones of melanoma cells or in HT1080 cells, was unable to stimulate DNA repair after UV irradiation or promote DNA-damage-induced apoptosis, indicating that H3K4me3 binding is necessary for these biological functions of ING1. Furthermore, N216S, V218I, and G221V mutations, found in human malignances, impair the ability of ING1 to associate with H3K4me3 or to induce nucleotide repair and cell death, linking the tumorigenic activity of ING1 with epigenetic regulation. Together, our findings reveal the critical role of the H3K4me3 interaction in mediating cellular responses to genotoxic stresses and offer new insight into the molecular mechanism underlying the tumor suppressive activity of ING1.",
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