Consistent with this idea, both KCMF1 and UBR4 were required for the survival of highly aneuploid cancer cell lines,33 with UBR4 essentiality correlating strongly with copy-number imbalances among protein complex subunits.34 Thus, a major role of the UBR4-KCMF1 complex is in maintaining cellular proteostasis via degradation of orphans, a large source of quality control substrates in cells. This evidence concerns the gene UBR4 and cancer.