Ubiquitylation of Ku80 by RNF126 Promotes Completion of Nonhomologous End Joining-Mediated DNA Repair

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...

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Published inMolecular and cellular biology Vol. 37; no. 4
Main Authors Ishida, Noriko, Nakagawa, Tadashi, Iemura, Shun-Ichiro, Yasui, Akira, Shima, Hiroki, Katoh, Yasutake, Nagasawa, Yuko, Natsume, Toru, Igarashi, Kazuhiko, Nakayama, Keiko
Format Journal Article
LanguageEnglish
Published United States Taylor & Francis 01.02.2017
American Society for Microbiology
Subjects
Animals
Chromatin - metabolism
DNA Breaks, Double-Stranded - radiation effects
DNA End-Joining Repair
DNA repair
HEK293 Cells
HeLa Cells
Humans
Ku Autoantigen - metabolism
Ku80
Mice
Models, Biological
NIH 3T3 Cells
nonhomologous end joining (NHEJ)
Protein Multimerization - radiation effects
Proteolysis - radiation effects
Radiation, Ionizing
RNF126
Ubiquitin-Protein Ligases - metabolism
Ubiquitination - radiation effects
ubiquitylation
nonhomologous end joining (NHEJ)
Ku80
RNF126
DNA repair
ubiquitylation
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Summary: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.
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N.I. and T.N. contributed equally to this study.
Citation Ishida N, Nakagawa T, Iemura S-I, Yasui A, Shima H, Katoh Y, Nagasawa Y, Natsume T, Igarashi K, Nakayama K. 2017. Ubiquitylation of Ku80 by RNF126 promotes completion of nonhomologous end joining-mediated DNA repair. Mol Cell Biol 37:e00347-16. https://doi.org/10.1128/MCB.00347-16.
Present address: Noriko Ishida, Department of Biobank, Tohoku Medical Megabank Organization, Tohoku University, Sendai, Miyagi, Japan; Shun-Ichiro Iemura, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan.
ISSN:1098-5549
0270-7306
1098-5549
DOI:10.1128/MCB.00347-16