The RNF138 E3 ligase displaces Ku to promote DNA end resection and regulate DNA repair pathway choice

  • Nat Cell Biol. 2015 Nov;17(11):1446-57. doi: 10.1038/ncb3259.
Ismail Hassan Ismail  1  2 ,  Jean-Philippe Gagné  3  4 ,  Marie-Michelle Genois  4  5 ,  Hilmar Strickfaden  1 ,  Darin McDonald  1 ,  Zhizhong Xu  1 ,  Guy G Poirier  3  4 ,  Jean-Yves Masson  4  5 ,  Michael J Hendzel  1
Affiliations
  • 1. Departments of Oncology and Cell Biology, Faculty of Medicine and Dentistry, University of Alberta, 11560 University Avenue Edmonton, Alberta T6G 1Z2, Canada.
  • 2. Biophysics Department, Faculty of Science, Cairo University, 12613 Giza, Egypt.
  • 3. CHU de Québec Research Center, CHUL Pavilion, Oncology Axis, 2705 boul. Laurier Québec city, Québec G1V 4G2, Canada.
  • 4. Department of Molecular Biology, Medical Biochemistry and Pathology, Laval University, Québec City, Québec G1V 0A6, Canada.
  • 5. Genome Stability Laboratory, CHU de Québec Research Center, HDQ Pavilion, Oncology Axis, 9 McMahon Québec City, Québec G1R 2J6, Canada.
PMID: 26502055 DOI: 10.1038/ncb3259
Abstract

DNA double-strand breaks (DSBs) are repaired mainly by non-homologous end joining or homologous recombination (HR). Cell cycle stage and DNA end resection are believed to regulate the commitment to HR repair. Here we identify RNF138 as a ubiquitin E3 Ligase that regulates the HR pathway. RNF138 is recruited to DNA damage sites through zinc fingers that have a strong preference for DNA with 5'- or 3'-single-stranded overhangs. RNF138 stimulates DNA end resection and promotes ATR-dependent signalling and DSB repair by HR, thereby contributing to cell survival on exposure to DSB-inducing agents. Finally, we establish that RNF138-dependent Ku removal from DNA breaks is one mechanism whereby RNF138 can promote HR. These results establish RNF138 as an important regulator of DSB repair pathway choice.