Two case studies (UBR5 and TRIM28) illustrate orthogonal modes of UPS rewiring: a mutation-driven axis in which <i>TP53</i>-mutant tumors elevate UBR5 to support replication stress tolerance, and a lineage-driven axis in which TRIM28 engages tissue-restricted regulatory networks with opposing prognostic effects in glioblastoma versus head and neck cancer. Here, TRIM28 is linked to head and neck cancer.