title: Ubiquitylation of Ku80 by RNF126 Promotes Completion of Nonhomologous End Joining-Mediated DNA Repair.
abstract: Repair of damaged DNA is critical for maintenance of genetic information. In eukaryotes, DNA double-strand breaks (DSBs) are recognized by the Ku70-Ku80 heterodimer, which then recruits proteins that mediate repair by nonhomologous end joining (NHEJ). Prolonged retention of Ku70/80 at DSBs prevents completion of repair, however, with ubiquitylation of Ku80 having been implicated in Ku70/80 dissociation from DNA. Here, we identify RNF126 as a ubiquitin ligase that is recruited to DSBs and ubiquitylates Ku80, with UBE2D3 serving as an E2 enzyme. Knockdown of RNF126 prevented Ku70/80 dissociation from DSBs and inhibited break repair. Attenuation of Ku80 ubiquitylation by replacement of ubiquitylation site lysines with arginine residues delayed Ku70/80 release from chromatin after DSB induction by genotoxic insults. Together, our data indicate that RNF126 is a novel regulator of NHEJ that promotes completion of DNA repair by ubiquitylating Ku80 and releasing Ku70/80 from damaged DNA.
authors.affiliation: Division of Cell Proliferation, ART, Graduate School of Medicine, Tohoku University, Sendai, Miyagi, Japan.
authors.forename: Noriko
authors.initials: N
authors.lastname: Ishida
authors.affiliation: Division of Cell Proliferation, ART, Graduate School of Medicine, Tohoku University, Sendai, Miyagi, Japan.
authors.forename: Tadashi
authors.initials: T
authors.lastname: Nakagawa
authors.affiliation: Biomedical Information Research Center, National Institute of Advanced Industrial Science and Technology, Tokyo, Japan.
authors.forename: Shun-Ichiro
authors.initials: SI
authors.lastname: Iemura
authors.affiliation: Division of Dynamic Proteome in Cancer and Aging, Institute of Development, Aging, and Cancer, Tohoku University, Sendai, Miyagi, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Yasui
authors.affiliation: Department of Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Shima
authors.affiliation: Department of Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan.
authors.forename: Yasutake
authors.initials: Y
authors.lastname: Katoh
authors.affiliation: Division of Cell Proliferation, ART, Graduate School of Medicine, Tohoku University, Sendai, Miyagi, Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Nagasawa
authors.affiliation: Biomedical Information Research Center, National Institute of Advanced Industrial Science and Technology, Tokyo, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Natsume
authors.affiliation: Department of Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Igarashi
authors.affiliation: Division of Cell Proliferation, ART, Graduate School of Medicine, Tohoku University, Sendai, Miyagi, Japan nakayak2@med.tohoku.ac.jp.
authors.forename: Keiko
authors.initials: K
authors.lastname: Nakayama
mesh_terms: D000818:Animals; D002843:Chromatin / Q000378:metabolism; D053903:DNA Breaks, Double-Stranded / Q000528:radiation effects; D059766:DNA End-Joining Repair; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D000072200:Ku Autoantigen / Q000378:metabolism*; D051379:Mice; D008954:Models, Biological; D041681:NIH 3T3 Cells; D055503:Protein Multimerization / Q000528:radiation effects; D059748:Proteolysis / Q000528:radiation effects; D011839:Radiation, Ionizing; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D054875:Ubiquitination / Q000528:radiation effects
chemical_list: D002843:Chromatin; C578829:RNF126 protein, human; D044767:Ubiquitin-Protein Ligases; D000072200:Ku Autoantigen
keywords: DNA repair; Ku80; RNF126; nonhomologous end joining (NHEJ); ubiquitylation