Plasticity of the cullin-RING ligase repertoire shapes sensitivity to ligand-induced protein degradation

Inducing protein degradation via small-molecules is a novel and transformative therapeutic paradigm. While structural requirements of target degradation are emerging, mechanisms determining the cellular response to small-molecule degraders remain poorly understood. To systematically delineate effectors required for target protein degradation, we applied genome-scale CRISPR/Cas9 screens for five drugs that hijack different substrate receptors (SRs) of cullin RING ligases (CRLs) for target protein degradation. We find that sensitivity to small-molecule degraders is dictated by shared and drug-specific modulator networks including the COP9 signalosome and the SR exchange factor CAND1. Genetic or pharmacologic perturbation of these effectors impairs CRL plasticity and arrests a wide array of ligases in a constitutively active state. Resulting defects in CRL decommissioning prompt widespread CRL auto-degradation that confers resistance to multiple degraders. Collectively, our study informs on regulation and architecture of CRLs amenable for target protein degradation, and outlines biomarkers and putative resistance mechanisms for upcoming clinical investigation.