title: Concerted activities of distinct H4K20 methyltransferases at DNA double-strand breaks regulate 53BP1 nucleation and NHEJ-directed repair.
abstract: Although selective binding of 53BP1 to dimethylated histone H4 lysine 20 (H4K20me2) at DNA double-strand breaks (DSBs) is a necessary and pivotal determinant of nonhomologous end joining (NHEJ)-directed repair, the enzymes that generate H4K20me2 at DSBs were unclear. Here, we determined that the PR-Set7 monomethyltransferase (H4K20me1) regulates de novo H4K20 methylation at DSBs. Rapid recruitment of PR-Set7 to DSBs was dependent on the NHEJ Ku70 protein and necessary for NHEJ-directed repair. PR-Set7 monomethyltransferase activity was required, but insufficient, for H4K20me2 and 53BP1 nucleation at DSBs. We determined that PR-Set7-mediated H4K20me1 facilitates Suv4-20 methyltransferase recruitment and catalysis to generate H4K20me2 necessary for 53BP1 binding. The orchestrated and concerted activities of PR-Set7 and Suv4-20 were required for proficient 53BP1 nucleation and DSB repair. This report identifies PR-Set7 as an essential component of NHEJ and implicates PR-Set7 as a central determinant of NHEJ-directed repair early in mammalian DSB repair pathway choice.
authors.affiliation: Department of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
authors.forename: Creighton T
authors.initials: CT
authors.lastname: Tuzon
authors.affiliation: Department of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
authors.forename: Tanya
authors.initials: T
authors.lastname: Spektor
authors.affiliation: Department of Biological Chemistry, School of Medicine, University of California at Irvine, Irvine, CA 92697, USA.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Kong
authors.affiliation: Department of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
authors.forename: Lauren M
authors.initials: LM
authors.lastname: Congdon
authors.affiliation: Department of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
authors.forename: Shumin
authors.initials: S
authors.lastname: Wu
authors.affiliation: Munich Center for Integrated Protein Science, Adolf-Butenandt-Institute, Ludwig Maximilian University, Munich 80336, Germany.
authors.forename: Gunnar
authors.initials: G
authors.lastname: Schotta
authors.affiliation: Department of Biological Chemistry, School of Medicine, University of California at Irvine, Irvine, CA 92697, USA.
authors.forename: Kyoko
authors.initials: K
authors.lastname: Yokomori
authors.affiliation: Department of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA. Electronic address: juddrice@usc.edu.
authors.forename: Judd C
authors.initials: JC
authors.lastname: Rice
mesh_terms: D021581:Active Transport, Cell Nucleus; D002467:Cell Nucleus / Q000378:metabolism*; D053903:DNA Breaks, Double-Stranded; D059766:DNA End-Joining Repair; D057809:HEK293 Cells; D006367:HeLa Cells; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D000071857:Tumor Suppressor p53-Binding Protein 1
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C498301:TP53BP1 protein, human; D000071857:Tumor Suppressor p53-Binding Protein 1; D011495:Histone-Lysine N-Methyltransferase