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Mol Cell. 2018 Mar 1;69(5):866-878.e7. doi: 10.1016/j.molcel.2018.02.002.

The Ubiquitin E3/E4 Ligase UBE4A Adjusts Protein Ubiquitylation and Accumulation at Sites of DNA Damage, Facilitating Double-Strand Break Repair.

Author information

1
The David and Inez Myers Laboratory for Cancer Research, Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
2
Cancer Research UK and Medical Research Council Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford, UK.
3
Perlmutter NYU Cancer Center and Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY, USA.
4
Centro Andaluz de Biología Molecular y Medicina Regenerativa (CABIMER) and Department of Genetics, University of Sevilla, Sevilla, Spain.
5
National Cancer Institute, NIH, Bethesda, MD, USA.
6
Departments of Pathology and Biochemistry and Molecular Biology, Dalhousie University, Halifax, NS, Canada.
7
Department of Biochemistry and Protein Network Research Center, Yonsei University, 134 Shinchon-Dong, Seodaemoon-Gu, Seoul, Korea.
8
State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
9
The David and Inez Myers Laboratory for Cancer Research, Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel. Electronic address: yossih@post.tau.ac.il.

Abstract

Double-strand breaks (DSBs) are critical DNA lesions that robustly activate the elaborate DNA damage response (DDR) network. We identified a critical player in DDR fine-tuning: the E3/E4 ubiquitin ligase UBE4A. UBE4A's recruitment to sites of DNA damage is dependent on primary E3 ligases in the DDR and promotes enhancement and sustainment of K48- and K63-linked ubiquitin chains at these sites. This step is required for timely recruitment of the RAP80 and BRCA1 proteins and proper organization of RAP80- and BRCA1-associated protein complexes at DSB sites. This pathway is essential for optimal end resection at DSBs, and its abrogation leads to upregulation of the highly mutagenic alternative end-joining repair at the expense of error-free homologous recombination repair. Our data uncover a critical regulatory level in the DSB response and underscore the importance of fine-tuning the complex DDR network for accurate and balanced execution of DSB repair.

KEYWORDS:

DNA damage; UBE4A; double-strand breaks; genome stability; ubiquitin

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