title: The COP9 signalosome is vital for timely repair of DNA double-strand breaks.
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.
authors: 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.
authors: Michal
authors: M
authors: Meir
authors: 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.
authors: Yaron
authors: Y
authors: Galanty
authors: 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.
authors: Lior
authors: L
authors: Kashani
authors: 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.
authors: Michael
authors: M
authors: Blank
authors: 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.
authors: Rami
authors: R
authors: Khosravi
authors: Centro Andaluz de Biología Molecular y Medicina Regenerativa (CABIMER) and Department of Genetics, University of Sevilla, Sevilla, 41092, Spain.
authors: María Jesús
authors: MJ
authors: Fernández-Ávila
authors: Centro Andaluz de Biología Molecular y Medicina Regenerativa (CABIMER) and Department of Genetics, University of Sevilla, Sevilla, 41092, Spain.
authors: Andrés
authors: A
authors: Cruz-García
authors: 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.
authors: Ayelet
authors: A
authors: Star
authors: 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.
authors: Lea
authors: L
authors: Shochot
authors: MRC Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences, University of Dundee, Dundee, DD1 5EH, Scotland, UK.
authors: Yann
authors: Y
authors: Thomas
authors: Genetics and Molecular Biology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, 20892, USA.
authors: Lisa J
authors: LJ
authors: Garrett
authors: Department of Molecular Biology and Ecology of Plants, George S. Wise Faculty of Life sciences, Tel Aviv University, Tel Aviv, 69978, Israel.
authors: Daniel A
authors: DA
authors: Chamovitz
authors: Genetics and Molecular Biology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, 20892, USA.
authors: David M
authors: DM
authors: Bodine
authors: MRC Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences, University of Dundee, Dundee, DD1 5EH, Scotland, UK.
authors: Thimo
authors: T
authors: Kurz
authors: Centro Andaluz de Biología Molecular y Medicina Regenerativa (CABIMER) and Department of Genetics, University of Sevilla, Sevilla, 41092, Spain.
authors: Pablo
authors: P
authors: Huertas
authors: 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.
authors: Yael
authors: Y
authors: Ziv
authors: 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.
authors: Yosef
authors: Y
authors: Shiloh
mesh_terms: D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism; D000075686:COP9 Signalosome Complex; D002460:Cell Line; D002478:Cells, Cultured; D044842:Cullin Proteins / Q000378:metabolism; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair; D006801:Humans; D051379:Mice; D046912:Multiprotein Complexes / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism; D010447:Peptide Hydrolases / Q000378:metabolism*; D011494:Protein Kinases / Q000378:metabolism
chemical_list: C114234:CUL4A protein, human; D044842:Cullin Proteins; D046912:Multiprotein Complexes; D009687:Nuclear Proteins; D011494:Protein Kinases; D064007:Ataxia Telangiectasia Mutated Proteins; D010447:Peptide Hydrolases; D000075686:COP9 Signalosome Complex