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

Michal Meir, Yaron Galanty (Lead / Corresponding author), 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 (Lead / Corresponding author), Yosef Shiloh (Lead / Corresponding author)

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    22 Citations (Scopus)

    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
    Early online date8 Apr 2015
    DOIs
    Publication statusPublished - 19 May 2015

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    Meir, M., Galanty, Y., Kashani, L., Blank, M., Khosravi, R., Fernández-Ávila, M. J., Cruz-García, A., Star, A., Shochot, L., Thomas, Y., Garrett, L. J., Chamovitz, D. A., Bodine, D. M., Kurz, T., Huertas, P., Ziv, Y., & Shiloh, Y. (2015). The COP9 signalosome is vital for timely repair of DNA double-strand breaks. Nucleic Acids Research, 43(9), 4517-4530. https://doi.org/10.1093/nar/gkv270