Journal
NATURE CHEMICAL BIOLOGY
Volume 13, Issue 3, Pages 317-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/NCHEMBIO.2282
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Funding
- AbbVie [1097737]
- Bayer Pharma AG
- Boehringer Ingelheim
- Canada Foundation for Innovation
- Eshelman Institute for Innovation
- Genome Canada
- Innovative Medicines Initiative (EU/EFPIA)
- Janssen
- Merck Co.
- Novartis Pharma AG
- Pfizer
- Sao Paulo Research Foundation-FAPESP
- Takeda
- Wellcome Trust
- National Institute of Mental Health's Psychoactive Drug Screening Program [HHSN-271-2013-00017-C]
- Industrial Macromolecular Crystallography Association
- Hauptman-Woodward Medical Research Institute
- US Department of Energy, Office of Science, Office of Basic Energy Sciences [DE-AC02-06CH11357]
- American Cancer Society [RSG117619]
- NCI Cancer Center Support Grant [P30CA014089]
- Deutsche Forschungsgemeinschaft [SFB1064/A11]
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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.
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