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

Meir, M. et al. (2015) The COP9 signalosome is vital for timely repair of DNA double-strand breaks. Nucleic Acids Research, 43(9), pp. 4517-4530. (doi: 10.1093/nar/gkv270) (PMID:25855810) (PMCID:PMC4482063)

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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.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Kurz, Dr Thimo
Authors: 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., and Shiloh, Y.
College/School:College of Medical Veterinary and Life Sciences > School of Molecular Biosciences
Journal Name:Nucleic Acids Research
Publisher:Oxford University Press
ISSN (Online):1362-4962
Published Online:08 April 2015
Copyright Holders:Copyright © 2015 The Authors
First Published:First published in Nucleic Acids Research 43(9): 4517-2530
Publisher Policy:Reproduced under a Creative Commons License

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