| Literature DB >> 28114273 |
Kenneth D Bromberg1, Taylor R H Mitchell2, Anup K Upadhyay1, Clarissa G Jakob1, Manisha A Jhala1, Kenneth M Comess1, Loren M Lasko1, Conglei Li3, Creighton T Tuzon4, Yujia Dai1, Fengling Li2, Mohammad S Eram2, Alexander Nuber5, Niru B Soni1, Vlasios Manaves1, Mikkel A Algire1, Ramzi F Sweis1, Maricel Torrent1, Gunnar Schotta5, Chaohong Sun1, Michael R Michaelides1, Alex R Shoemaker1, Cheryl H Arrowsmith2, Peter J Brown2, Vijayaratnam Santhakumar2, Alberto Martin3, Judd C Rice4, Gary G Chiang1,6, Masoud Vedadi2,7, Dalia Barsyte-Lovejoy2, William N Pappano1.
Abstract
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.Entities:
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Year: 2017 PMID： 28114273 DOI： 10.1038/nchembio.2282
Source DB: PubMed Journal: Nat Chem Biol ISSN： 1552-4450 Impact factor: 15.040