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 Resjournal_title
Nucleic acids researchauthors
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 Ydoi
10.1093/nar/gkv270subject
Has Abstractpub_date
2015-05-19 00:00:00pages
4517-30issue
9eissn
0305-1048issn
1362-4962pii
gkv270journal_volume
43pub_type
杂志文章abstract::Escherichia coli cells lacking the ribosomal RNA processing enzyme RNase III do no excise the normal RNA precursors p16a (17S) and p23a from nascent rRNA transcripts. These cells produce, instead, slightly larger p16b and p23b precursors. Digestion of p16b or p23b rRNA with RNases A plus T1 yields double-stranded frag...
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journal_title:Nucleic acids research
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journal_title:Nucleic acids research
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