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

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

Research output: Contribution to journalArticlepeer-review

27 Scopus citations

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.

Original languageEnglish
Pages (from-to)4517-4530
Number of pages14
JournalNucleic Acids Research
Volume43
Issue number9
DOIs
StatePublished - 17 Mar 2015
Externally publishedYes

ASJC Scopus subject areas

  • Genetics

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