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

Nat Chem Biol. 2017 Mar;13(3):317-324. doi: 10.1038/nchembio.2282. Epub 2017 Jan 23.


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.

MeSH terms

  • Cell Line, Tumor
  • Crystallography, X-Ray
  • DNA Repair / drug effects
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Epigenesis, Genetic / drug effects*
  • Genomic Instability / drug effects*
  • Heterocyclic Compounds, 4 or More Rings / chemistry
  • Heterocyclic Compounds, 4 or More Rings / pharmacology*
  • Histone-Lysine N-Methyltransferase / antagonists & inhibitors*
  • Histone-Lysine N-Methyltransferase / metabolism
  • Humans
  • Methylation / drug effects
  • Models, Molecular
  • Molecular Structure


  • A-196 compound
  • Enzyme Inhibitors
  • Heterocyclic Compounds, 4 or More Rings
  • Histone-Lysine N-Methyltransferase
  • KMT5C protein, human

Associated data

  • PubChem-Substance/321903808
  • PubChem-Substance/321903809
  • PubChem-Substance/321903810
  • PubChem-Substance/321903811
  • PubChem-Substance/321903812
  • PubChem-Substance/321903813
  • PubChem-Substance/321903814
  • PubChem-Substance/321903815
  • PubChem-Substance/321903816