Protein interactome homeostasis through an N-recognin E3 ligase is a vulnerability in aneuploid cancer

Aneuploidy and resulting gene copy number alterations (CNAs) are important hallmarks of human cancers. Since CNAs are not associated with dosage compensation in mRNA expression, cancer cells with a high CNA burden must harbor mechanisms to mitigate proteotoxic stress resulting from stoichiometric imbalance and accumulation of unfolded proteins ( 1 ). Here, we show that aneuploid human cancer cells exhibit discordance between CNAs and protein levels due to compensation at the proteome level, mainly concerning multi-protein complexes. Moreover, we identify the N-recognin ubiquitin ligase UBR4 as a critical mediator of protein interactome homeostasis that is essential for viability, specifically in highly aneuploid cancers in vitro and in vivo . UBR4 prunes the proteome to ensure the balanced expression of protein complex members. Inactivation of UBR4 in highly aneuploid cancer cells causes a convergence of copy number and protein levels and induces proteotoxic stress pathways. UBR4 inhibition may present a broadly applicable therapeutic strategy for cancer and other diseases driven by aneuploidy. One-Sentence Summary The N-recognin ubiquitin ligase UBR4 as a critical mediator of protein interactome homeostasis that is essential for viability in aneuploid cancers.