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Neddylation promotes ubiquitylation and release of Ku from DNA-damage sites.
- Source :
-
Cell reports [Cell Rep] 2015 May 05; Vol. 11 (5), pp. 704-14. Date of Electronic Publication: 2015 Apr 23. - Publication Year :
- 2015
-
Abstract
- The activities of many DNA-repair proteins are controlled through reversible covalent modification by ubiquitin and ubiquitin-like molecules. Nonhomologous end-joining (NHEJ) is the predominant DNA double-strand break (DSB) repair pathway in mammalian cells and is initiated by DSB ends being recognized by the Ku70/Ku80 (Ku) heterodimer. By using MLN4924, an anti-cancer drug in clinical trials that specifically inhibits conjugation of the ubiquitin-like protein, NEDD8, to target proteins, we demonstrate that NEDD8 accumulation at DNA-damage sites is a highly dynamic process. In addition, we show that depleting cells of the NEDD8 E2-conjugating enzyme, UBE2M, yields ionizing radiation hypersensitivity and reduced cell survival following NHEJ. Finally, we demonstrate that neddylation promotes Ku ubiquitylation after DNA damage and release of Ku and Ku-associated proteins from damage sites following repair. These studies provide insights into how the NHEJ core complex dissociates from repair sites and highlight its importance for cell survival following DSB induction.<br /> (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)
- Subjects :
- Antigens, Nuclear chemistry
Cell Line
Cell Survival drug effects
Cyclopentanes toxicity
DNA End-Joining Repair
DNA-Binding Proteins chemistry
Histones metabolism
Humans
Ku Autoantigen
NEDD8 Protein
Protein Binding
Protein Structure, Tertiary
Proteomics
Pyrimidines toxicity
RNA Interference
RNA, Small Interfering metabolism
Radiation, Ionizing
Ubiquitin-Conjugating Enzymes antagonists & inhibitors
Ubiquitin-Conjugating Enzymes genetics
Ubiquitin-Conjugating Enzymes metabolism
Ubiquitination drug effects
Ubiquitins antagonists & inhibitors
Antigens, Nuclear metabolism
DNA Damage drug effects
DNA Damage radiation effects
DNA-Binding Proteins metabolism
Ubiquitins metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 2211-1247
- Volume :
- 11
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Cell reports
- Publication Type :
- Academic Journal
- Accession number :
- 25921528
- Full Text :
- https://doi.org/10.1016/j.celrep.2015.03.058