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Nucleic Acids Res. 2015 May 19;43(9):4517-30. doi: 10.1093/nar/gkv270. Epub 2015 Apr 8.

The COP9 signalosome is vital for timely repair of DNA double-strand breaks.

Author information

1
The David and Inez Myers Laboratory for Cancer Research, Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, George S. Wise Faculty of Life sciences, Tel Aviv University, Tel Aviv, 69978 Israel.
2
The David and Inez Myers Laboratory for Cancer Research, Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, George S. Wise Faculty of Life sciences, Tel Aviv University, Tel Aviv, 69978 Israel y.galanty@gurdon.cam.ac.uk.
3
Centro Andaluz de Biología Molecular y Medicina Regenerativa (CABIMER) and Department of Genetics, University of Sevilla, Sevilla, 41092, Spain.
4
MRC Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences, University of Dundee, Dundee, DD1 5EH, Scotland, UK.
5
Genetics and Molecular Biology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, 20892, USA.
6
Department of Molecular Biology and Ecology of Plants, George S. Wise Faculty of Life sciences, Tel Aviv University, Tel Aviv, 69978, Israel.
7
The David and Inez Myers Laboratory for Cancer Research, Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, George S. Wise Faculty of Life sciences, Tel Aviv University, Tel Aviv, 69978 Israel yaelz@post.tau.ac.il.
8
The David and Inez Myers Laboratory for Cancer Research, Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, George S. Wise Faculty of Life sciences, Tel Aviv University, Tel Aviv, 69978 Israel yossih@post.tau.ac.il.

Abstract

The DNA damage response is vigorously activated by DNA double-strand breaks (DSBs). The chief mobilizer of the DSB response is the ATM protein kinase. We discovered that the COP9 signalosome (CSN) is a crucial player in the DSB response and an ATM target. CSN is a protein complex that regulates the activity of cullin ring ubiquitin ligase (CRL) complexes by removing the ubiquitin-like protein, NEDD8, from their cullin scaffold. We find that the CSN is physically recruited to DSB sites in a neddylation-dependent manner, and is required for timely repair of DSBs, affecting the balance between the two major DSB repair pathways-nonhomologous end-joining and homologous recombination repair (HRR). The CSN is essential for the processivity of deep end-resection-the initial step in HRR. Cullin 4a (CUL4A) is recruited to DSB sites in a CSN- and neddylation-dependent manner, suggesting that CSN partners with CRL4 in this pathway. Furthermore, we found that ATM-mediated phosphorylation of CSN subunit 3 on S410 is critical for proper DSB repair, and that loss of this phosphorylation site alone is sufficient to cause a DDR deficiency phenotype in the mouse. This novel branch of the DSB response thus significantly affects genome stability.

PMID:
25855810
PMCID:
PMC4482063
DOI:
10.1093/nar/gkv270
[Indexed for MEDLINE]
Free PMC Article

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