title: The SUV4-20 inhibitor A-196 verifies a role for epigenetics in genomic integrity.
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.
authors.affiliation: Discovery, Research and Development, AbbVie, North Chicago, Illinois, USA.
authors.forename: Kenneth D
authors.initials: KD
authors.lastname: Bromberg
authors.affiliation: Structural Genomics Consortium, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Taylor R H
authors.initials: TR
authors.lastname: Mitchell
authors.affiliation: Discovery, Research and Development, AbbVie, North Chicago, Illinois, USA.
authors.forename: Anup K
authors.initials: AK
authors.lastname: Upadhyay
authors.affiliation: Discovery, Research and Development, AbbVie, North Chicago, Illinois, USA.
authors.forename: Clarissa G
authors.initials: CG
authors.lastname: Jakob
authors.affiliation: Discovery, Research and Development, AbbVie, North Chicago, Illinois, USA.
authors.forename: Manisha A
authors.initials: MA
authors.lastname: Jhala
authors.affiliation: Discovery, Research and Development, AbbVie, North Chicago, Illinois, USA.
authors.forename: Kenneth M
authors.initials: KM
authors.lastname: Comess
authors.affiliation: Discovery, Research and Development, AbbVie, North Chicago, Illinois, USA.
authors.forename: Loren M
authors.initials: LM
authors.lastname: Lasko
authors.affiliation: Department of Immunology, University of Toronto, Medical Sciences Building, Toronto, Canada.
authors.forename: Conglei
authors.initials: C
authors.lastname: Li
authors.affiliation: Department of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California, USA.
authors.forename: Creighton T
authors.identifier: 0000-0001-9706-610X
authors.initials: CT
authors.lastname: Tuzon
authors.affiliation: Discovery, Research and Development, AbbVie, North Chicago, Illinois, USA.
authors.forename: Yujia
authors.initials: Y
authors.lastname: Dai
authors.affiliation: Structural Genomics Consortium, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Fengling
authors.initials: F
authors.lastname: Li
authors.affiliation: Structural Genomics Consortium, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Mohammad S
authors.initials: MS
authors.lastname: Eram
authors.affiliation: Ludwig-Maximilians-Universität München and Munich Center for Integrated Protein Science (CiPSM), Biomedical Center, Planegg-Martinsried, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Nuber
authors.affiliation: Discovery, Research and Development, AbbVie, North Chicago, Illinois, USA.
authors.forename: Niru B
authors.initials: NB
authors.lastname: Soni
authors.affiliation: Discovery, Research and Development, AbbVie, North Chicago, Illinois, USA.
authors.forename: Vlasios
authors.initials: V
authors.lastname: Manaves
authors.affiliation: Discovery, Research and Development, AbbVie, North Chicago, Illinois, USA.
authors.forename: Mikkel A
authors.initials: MA
authors.lastname: Algire
authors.affiliation: Discovery, Research and Development, AbbVie, North Chicago, Illinois, USA.
authors.forename: Ramzi F
authors.initials: RF
authors.lastname: Sweis
authors.affiliation: Discovery, Research and Development, AbbVie, North Chicago, Illinois, USA.
authors.forename: Maricel
authors.initials: M
authors.lastname: Torrent
authors.affiliation: Ludwig-Maximilians-Universität München and Munich Center for Integrated Protein Science (CiPSM), Biomedical Center, Planegg-Martinsried, Germany.
authors.forename: Gunnar
authors.identifier: 0000-0003-4940-6135
authors.initials: G
authors.lastname: Schotta
authors.affiliation: Discovery, Research and Development, AbbVie, North Chicago, Illinois, USA.
authors.forename: Chaohong
authors.initials: C
authors.lastname: Sun
authors.affiliation: Discovery, Research and Development, AbbVie, North Chicago, Illinois, USA.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Michaelides
authors.affiliation: Discovery, Research and Development, AbbVie, North Chicago, Illinois, USA.
authors.forename: Alex R
authors.initials: AR
authors.lastname: Shoemaker
authors.affiliation: Structural Genomics Consortium, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Cheryl H
authors.initials: CH
authors.lastname: Arrowsmith
authors.affiliation: Structural Genomics Consortium, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Brown
authors.affiliation: Structural Genomics Consortium, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Vijayaratnam
authors.initials: V
authors.lastname: Santhakumar
authors.affiliation: Department of Immunology, University of Toronto, Medical Sciences Building, Toronto, Canada.
authors.forename: Alberto
authors.initials: A
authors.lastname: Martin
authors.affiliation: Department of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California, USA.
authors.forename: Judd C
authors.initials: JC
authors.lastname: Rice
authors.affiliation: Discovery, Research and Development, AbbVie, North Chicago, Illinois, USA.|eFFECTOR Therapeutics, San Diego, California, USA.
authors.forename: Gary G
authors.identifier: 0000-0003-3004-7400
authors.initials: GG
authors.lastname: Chiang
authors.affiliation: Structural Genomics Consortium, University of Toronto, Toronto, Ontario, Canada.|Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Masoud
authors.initials: M
authors.lastname: Vedadi
authors.affiliation: Structural Genomics Consortium, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Dalia
authors.initials: D
authors.lastname: Barsyte-Lovejoy
authors.affiliation: Discovery, Research and Development, AbbVie, North Chicago, Illinois, USA.
authors.forename: William N
authors.initials: WN
authors.lastname: Pappano
mesh_terms: D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D004260:DNA Repair / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D044127:Epigenesis, Genetic / Q000187:drug effects*; D042822:Genomic Instability / Q000187:drug effects*; D006576:Heterocyclic Compounds, 4 or More Rings / Q000737:chemistry / Q000494:pharmacology*; D011495:Histone-Lysine N-Methyltransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D008745:Methylation / Q000187:drug effects; D008958:Models, Molecular; D015394:Molecular Structure
chemical_list: C000618381:A-196 compound; D004791:Enzyme Inhibitors; D006576:Heterocyclic Compounds, 4 or More Rings; D011495:Histone-Lysine N-Methyltransferase; C542918:KMT5C protein, human