5CPR

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

Summary for 5CPR

• Entry DOI: 10.2210/pdb5cpr/pdb
• Descriptor: Histone-lysine N-methyltransferase SUV420H1, ZINC ION, S-ADENOSYLMETHIONINE, ... (5 entities in total)
• Functional Keywords: protein lysine transferase, h4k20, non-homologous end joining, transferase
• Biological source: Homo sapiens (Human)
• Cellular location: Nucleus : Q4FZB7
• Total number of polymer chains: 1
• Total formula weight: 31748.09

Authors

Jakob, C.G.,Upadhyay, A.K.,Sun, C. (deposition date: 2015-07-21, release date: 2017-01-25, Last modification date: 2023-09-27)

Primary citation

Bromberg, K.D.,Mitchell, T.R.,Upadhyay, A.K.,Jakob, C.G.,Jhala, M.A.,Comess, K.M.,Lasko, L.M.,Li, C.,Tuzon, C.T.,Dai, Y.,Li, F.,Eram, M.S.,Nuber, A.,Soni, N.B.,Manaves, V.,Algire, M.A.,Sweis, R.F.,Torrent, M.,Schotta, G.,Sun, C.,Michaelides, M.R.,Shoemaker, A.R.,Arrowsmith, C.H.,Brown, P.J.,Santhakumar, V.,Martin, A.,Rice, J.C.,Chiang, G.G.,Vedadi, M.,Barsyte-Lovejoy, D.,Pappano, W.N.
The SUV4-20 inhibitor A-196 verifies a role for epigenetics in genomic integrity.
Nat. Chem. Biol., 13:317-324, 2017

PubMed 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.

PubMed: 28114273
DOI: 10.1038/nchembio.2282

Experimental method

X-RAY DIFFRACTION (2.22 Å)