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

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^FBXO5-APC/C-GMNN and CUL4^DTL-SETD8, that contribute substantially to the toxicity of CSN inhibition. Our data highlight th

SUBMITTER: Zhang Y 

PROVIDER: S-EPMC9456757 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature