5cpr | pdb_00005cpr
The novel SUV4-20 inhibitor A-196 verifies a role for epigenetics in genomic integrity
Structural highlights
FunctionKMT5B_HUMAN Histone methyltransferase that specifically trimethylates 'Lys-20' of histone H4. H4 'Lys-20' trimethylation represents a specific tag for epigenetic transcriptional repression. Mainly functions in pericentric heterochromatin regions, thereby playing a central role in the establishment of constitutive heterochromatin in these regions. KMT5B is targeted to histone H3 via its interaction with RB1 family proteins (RB1, RBL1 and RBL2) (By similarity). Plays a role in myogenesis by regulating the expression of target genes, such as EID3.[1] Publication Abstract from PubMedProtein 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. The SUV4-20 inhibitor A-196 verifies a role for epigenetics in genomic integrity.,Bromberg KD, Mitchell TR, Upadhyay AK, Jakob CG, Jhala MA, Comess KM, Lasko LM, Li C, Tuzon CT, Dai Y, Li F, Eram MS, Nuber A, Soni NB, Manaves V, Algire MA, Sweis RF, Torrent M, Schotta G, Sun C, Michaelides MR, Shoemaker AR, Arrowsmith CH, Brown PJ, Santhakumar V, Martin A, Rice JC, Chiang GG, Vedadi M, Barsyte-Lovejoy D, Pappano WN Nat Chem Biol. 2017 Mar;13(3):317-324. doi: 10.1038/nchembio.2282. Epub 2017 Jan , 23. PMID:28114273[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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