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Adaptive exchange sustains cullin-RING ubiquitin ligase networks and proper licensing of DNA replication.

Authors :
Zhang Y
Jost M
Pak RA
Lu D
Li J
Lomenick B
Garbis SD
Li CM
Weissman JS
Lipford JR
Deshaies RJ
Source :
Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2022 Sep 06; Vol. 119 (36), pp. e2205608119. Date of Electronic Publication: 2022 Aug 29.
Publication Year :
2022

Abstract

Cop9 signalosome (CSN) regulates the function of cullin-RING E3 ubiquitin ligases (CRLs) by deconjugating the ubiquitin-like protein NEDD8 from the cullin subunit. To understand the physiological impact of CSN function on the CRL network and cell proliferation, we combined quantitative mass spectrometry and genome-wide CRISPR interference (CRISPRi) and CRISPR activation (CRISPRa) screens to identify factors that modulate cell viability upon inhibition of CSN by the small molecule CSN5i-3. CRL components and regulators strongly modulated the antiproliferative effects of CSN5i-3, and in addition we found two pathways involved in genome integrity, SCF <superscript>FBXO5</superscript> -APC/C-GMNN and CUL4 <superscript>DTL</superscript> -SETD8, that contribute substantially to the toxicity of CSN inhibition. Our data highlight the importance of CSN-mediated NEDD8 deconjugation and adaptive exchange of CRL substrate receptors in sustaining CRL function and suggest approaches for leveraging CSN inhibition for the treatment of cancer.

Details

Language :
English
ISSN :
1091-6490
Volume :
119
Issue :
36
Database :
MEDLINE
Journal :
Proceedings of the National Academy of Sciences of the United States of America
Publication Type :
Academic Journal
Accession number :
36037385
Full Text :
https://doi.org/10.1073/pnas.2205608119