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

Michal Meir, Yaron Galanty, Lior Kashani, Michael Blank, Rami Khosravi, María Jesús Fernández-Ávila, Andrés Cruz-García, Ayelet Star, Lea Shochot, Yann Thomas, Lisa J Garrett, Daniel A Chamovitz, David M Bodine, Thimo Kurz, Pablo Huertas, Yael Ziv, Yosef Shiloh

Index: Nucleic Acids Res. 43 , 4517-30, (2015)

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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. © The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research.