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

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

  • Nat Chem Biol. 2017 Mar;13(3):317-324. doi: 10.1038/nchembio.2282.
Kenneth D Bromberg 1,  Taylor R H Mitchell 2,  Anup K Upadhyay 1,  Clarissa G Jakob 1,  Manisha A Jhala 1,  Kenneth M Comess 1,  Loren M Lasko 1,  Conglei Li 3,  Creighton T Tuzon 4,  Yujia Dai 1,  Fengling Li 2,  Mohammad S Eram 2,  Alexander Nuber 5,  Niru B Soni 1,  Vlasios Manaves 1,  Mikkel A Algire 1,  Ramzi F Sweis 1,  Maricel Torrent 1,  Gunnar Schotta 5,  Chaohong Sun 1,  Michael R Michaelides 1,  Alex R Shoemaker 1,  Cheryl H Arrowsmith 2,  Peter J Brown 2,  Vijayaratnam Santhakumar 2,  Alberto Martin 3,  Judd C Rice 4,  Gary G Chiang 1 6,  Masoud Vedadi 2 7,  Dalia Barsyte-Lovejoy 2,  William N Pappano 1
Affiliations

Affiliations

  • 1 Discovery, Research and Development, AbbVie, North Chicago, Illinois, USA.
  • 2 Structural Genomics Consortium, University of Toronto, Toronto, Ontario, Canada.
  • 3 Department of Immunology, University of Toronto, Medical Sciences Building, Toronto, Canada.
  • 4 Department of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California, USA.
  • 5 Ludwig-Maximilians-Universität München and Munich Center for Integrated Protein Science (CiPSM), Biomedical Center, Planegg-Martinsried, Germany.
  • 6 eFFECTOR Therapeutics, San Diego, California, USA.
  • 7 Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada.
PMID: 28114273 DOI: 10.1038/nchembio.2282
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.

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