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

TY - JOUR

T1 - The COP9 signalosome is vital for timely repair of DNA double-strand breaks

AU - Meir, Michal

AU - Galanty, Yaron

AU - Kashani, Lior

AU - Blank, Michael

AU - Khosravi, Rami

AU - Fernández-Ávila, María Jesús

AU - Cruz-García, Andrés

AU - Star, Ayelet

AU - Shochot, Lea

AU - Thomas, Yann

AU - Garrett, Lisa J.

AU - Chamovitz, Daniel A.

AU - Bodine, David M.

AU - Kurz, Thimo

AU - Huertas, Pablo

AU - Ziv, Yael

AU - Shiloh, Yosef

N1 - © The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research.

PY - 2015/5/19

Y1 - 2015/5/19

N2 - 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.

AB - 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.

U2 - 10.1093/nar/gkv270

DO - 10.1093/nar/gkv270

M3 - Article

C2 - 25855810

SN - 0305-1048

VL - 43

SP - 4517

EP - 4530

JO - Nucleic Acids Research

JF - Nucleic Acids Research

IS - 9

ER -