The SUV4-20 inhibitor A-196 verifies a role for epigenetics in genomic integrity.

Autor: Bromberg KD; Discovery, Research and Development, AbbVie, North Chicago, Illinois, USA., Mitchell TR; Structural Genomics Consortium, University of Toronto, Toronto, Ontario, Canada., Upadhyay AK; Discovery, Research and Development, AbbVie, North Chicago, Illinois, USA., Jakob CG; Discovery, Research and Development, AbbVie, North Chicago, Illinois, USA., Jhala MA; Discovery, Research and Development, AbbVie, North Chicago, Illinois, USA., Comess KM; Discovery, Research and Development, AbbVie, North Chicago, Illinois, USA., Lasko LM; Discovery, Research and Development, AbbVie, North Chicago, Illinois, USA., Li C; Department of Immunology, University of Toronto, Medical Sciences Building, Toronto, Canada., Tuzon CT; Department of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California, USA., Dai Y; Discovery, Research and Development, AbbVie, North Chicago, Illinois, USA., Li F; Structural Genomics Consortium, University of Toronto, Toronto, Ontario, Canada., Eram MS; Structural Genomics Consortium, University of Toronto, Toronto, Ontario, Canada., Nuber A; Ludwig-Maximilians-Universität München and Munich Center for Integrated Protein Science (CiPSM), Biomedical Center, Planegg-Martinsried, Germany., Soni NB; Discovery, Research and Development, AbbVie, North Chicago, Illinois, USA., Manaves V; Discovery, Research and Development, AbbVie, North Chicago, Illinois, USA., Algire MA; Discovery, Research and Development, AbbVie, North Chicago, Illinois, USA., Sweis RF; Discovery, Research and Development, AbbVie, North Chicago, Illinois, USA., Torrent M; Discovery, Research and Development, AbbVie, North Chicago, Illinois, USA., Schotta G; Ludwig-Maximilians-Universität München and Munich Center for Integrated Protein Science (CiPSM), Biomedical Center, Planegg-Martinsried, Germany., Sun C; Discovery, Research and Development, AbbVie, North Chicago, Illinois, USA., Michaelides MR; Discovery, Research and Development, AbbVie, North Chicago, Illinois, USA., Shoemaker AR; Discovery, Research and Development, AbbVie, North Chicago, Illinois, USA., Arrowsmith CH; Structural Genomics Consortium, University of Toronto, Toronto, Ontario, Canada., Brown PJ; Structural Genomics Consortium, University of Toronto, Toronto, Ontario, Canada., Santhakumar V; Structural Genomics Consortium, University of Toronto, Toronto, Ontario, Canada., Martin A; Department of Immunology, University of Toronto, Medical Sciences Building, Toronto, Canada., Rice JC; Department of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California, USA., Chiang GG; Discovery, Research and Development, AbbVie, North Chicago, Illinois, USA.; eFFECTOR Therapeutics, San Diego, California, USA., Vedadi M; Structural Genomics Consortium, University of Toronto, Toronto, Ontario, Canada.; Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada., Barsyte-Lovejoy D; Structural Genomics Consortium, University of Toronto, Toronto, Ontario, Canada., Pappano WN; Discovery, Research and Development, AbbVie, North Chicago, Illinois, USA.
Jazyk: angličtina
Zdroj: Nature chemical biology [Nat Chem Biol] 2017 Mar; Vol. 13 (3), pp. 317-324. Date of Electronic Publication: 2017 Jan 23.
DOI: 10.1038/nchembio.2282
Abstrakt: Protein lysine methyltransferases (PKMTs) regulate diverse physiological processes including transcription and the maintenance of genomic integrity. Genetic studies suggest that the PKMTs SUV420H1 and SUV420H2 facilitate proficient nonhomologous end-joining (NHEJ)-directed DNA repair by catalyzing the di- and trimethylation (me2 and me3, respectively) of lysine 20 on histone 4 (H4K20). Here we report the identification of A-196, a potent and selective inhibitor of SUV420H1 and SUV420H2. Biochemical and co-crystallization analyses demonstrate that A-196 is a substrate-competitive inhibitor of both SUV4-20 enzymes. In cells, A-196 induced a global decrease in H4K20me2 and H4K20me3 and a concomitant increase in H4K20me1. A-196 inhibited 53BP1 foci formation upon ionizing radiation and reduced NHEJ-mediated DNA-break repair but did not affect homology-directed repair. These results demonstrate the role of SUV4-20 enzymatic activity in H4K20 methylation and DNA repair. A-196 represents a first-in-class chemical probe of SUV4-20 to investigate the role of histone methyltransferases in genomic integrity.
Databáze: MEDLINE
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