Concerted Activities of Distinct H4K20 Methyltransferases at DNA Double-Strand Breaks Regulate 53BP1 Nucleation and NHEJ-Directed Repair

Tuzon, Creighton T.; Spektor, Tanya; Kong, Xiaodong; Congdon, Lauren M.; Wu, Shumin; Schotta, Gunnar; Yokomori, Kyoko und Rice, Judd C. (2014): Concerted Activities of Distinct H4K20 Methyltransferases at DNA Double-Strand Breaks Regulate 53BP1 Nucleation and NHEJ-Directed Repair. In: Cell Reports, Bd. 8, Nr. 2: S. 429-437

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.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin > Adolf-Butenandt-Institut
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 2211-1247
• Sprache: Englisch