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

Bromberg, Kenneth D.; Mitchell, Taylor R. H.; Upadhyay, Anup K.; Jakob, Clarissa G.; Jhala, Manisha A.; Comess, Kenneth M.; Lasko, Loren M.; Li, Conglei; Tuzon, Creighton T.; Dai, Yujia; Li, Fengling; Eram, Mohammad S.; Nuber, Alexander; Soni, Niru B.; Manaves, Vlasios; Algire, Mikkel A.; Sweis, Ramzi F.; Torrent, Maricel; Schotta, Gunnar; Sun, Chaohong; Michaelides, Michael R.; Shoemaker, Alex R.; Arrowsmith, Cheryl H.; Brown, Peter J.; Santhakumar, Vijayaratnam; Martin, Alberto; Rice, Judd C.; Chiang, Gary G.; Vedadi, Masoud; Barsyte-Lovejoy, Dalia und Pappano, William N. (2017): The SUV4-20 inhibitor A-196 verifies a role for epigenetics in genomic integrity. In: Nature Chemical Biology, Bd. 13, Nr. 3: 317-+

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 non-homologous 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.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 1552-4450
• Sprache: Englisch