Inhibition of histone binding by supramolecular hosts.

Autor:	Allen HF; Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO 80045, U.S.A., Daze KD; †Department of Chemistry, University of Victoria, Victoria, BC, Canada, V8W 3V6., Shimbo T; ‡Laboratory of Molecular Carcinogenesis, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, U.S.A., Lai A; ‡Laboratory of Molecular Carcinogenesis, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, U.S.A., Musselman CA; Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO 80045, U.S.A., Sims JK; ‡Laboratory of Molecular Carcinogenesis, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, U.S.A., Wade PA; ‡Laboratory of Molecular Carcinogenesis, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, U.S.A., Hof F; †Department of Chemistry, University of Victoria, Victoria, BC, Canada, V8W 3V6., Kutateladze TG; Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO 80045, U.S.A.
Jazyk:	angličtina
Zdroj:	The Biochemical journal [Biochem J] 2014 May 01; Vol. 459 (3), pp. 505-12.
DOI:	10.1042/BJ20140145
Abstrakt:	The tandem PHD (plant homeodomain) fingers of the CHD4 (chromodomain helicase DNA-binding protein 4) ATPase are epigenetic readers that bind either unmodified histone H3 tails or H3K9me3 (histone H3 trimethylated at Lys⁹). This dual function is necessary for the transcriptional and chromatin remodelling activities of the NuRD (nucleosome remodelling and deacetylase) complex. In the present paper, we show that calixarene-based supramolecular hosts disrupt binding of the CHD4 PHD2 finger to H3K9me3, but do not affect the interaction of this protein with the H3K9me0 (unmodified histone H3) tail. A similar inhibitory effect, observed for the association of chromodomain of HP1γ (heterochromatin protein 1γ) with H3K9me3, points to a general mechanism of methyl-lysine caging by calixarenes and suggests a high potential for these compounds in biochemical applications. Immunofluorescence analysis reveals that the supramolecular agents induce changes in chromatin organization that are consistent with their binding to and disruption of H3K9me3 sites in living cells. The results of the present study suggest that the aromatic macrocyclic hosts can be used as a powerful new tool for characterizing methylation-driven epigenetic mechanisms.
Databáze:	MEDLINE
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