| Full text | |
| Author(s): Show less - |
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.
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Nuber, Alexander
;
Soni, Niru B.
;
Manaves, Vlasios
;
Algire, Mikkel A.
;
Sweis, Ramzi F.
;
Torrent, Maricel
;
Schotta, Gunnar
;
Sun, Chaohong
;
Michaelides, Michael R.
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Shoemaker, Alex R.
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Arrowsmith, Cheryl H.
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Brown, Peter J.
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Santhakumar, Vijayaratnam
;
Martin, Alberto
;
Rice, Judd C.
;
Chiang, Gary G.
;
Vedadi, Masoud
;
Barsyte-Lovejoy, Dalia
;
Pappano, William N.
Total Authors: 31
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| Document type: | Journal article |
| Source: | Nature Chemical Biology; v. 13, n. 3, p. 317+, MAR 2017. |
| Web of Science Citations: | 31 |
| 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. (AU) | |