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

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.

journal_name

Nucleic Acids Res

journal_title

Nucleic acids research

authors

Meir M,Galanty Y,Kashani L,Blank M,Khosravi R,Fernández-Ávila MJ,Cruz-García A,Star A,Shochot L,Thomas Y,Garrett LJ,Chamovitz DA,Bodine DM,Kurz T,Huertas P,Ziv Y,Shiloh Y

doi

10.1093/nar/gkv270

subject

Has Abstract

pub_date

2015-05-19 00:00:00

pages

4517-30

issue

9

eissn

0305-1048

issn

1362-4962

pii

gkv270

journal_volume

43

pub_type

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