TOPORS is a dual E3 ubiquitin and SUMO ligase that functions as a SUMO-targeted ubiquitin ligase (STUbL) with roles in DNA damage response and protein quality control. 1 As a STUbL, TOPORS combines ubiquitin ligase activity through its RING domain with poly-SUMO binding via SUMO-interacting motifs, functioning as a SUMO1-selective enzyme that complements RNF4 in generating complex ubiquitin landscapes on SUMOylated targets. 1 Mechanistically, TOPORS promotes resolution of DNA-protein crosslinks (DPCs) by recognizing SUMOylated substrates and targeting them for proteasomal degradation. 2 This function is particularly critical for resolving DNA methyltransferase 1 (DNMT1)-DPCs induced by hypomethylating agents and decitabine treatment. 32 TOPORS also mediates SUMO-dependent degradation of the oncogenic PML fusion protein in response to arsenic treatment in acute promyelocytic leukemia. 4 Clinically, TOPORS loss-of-function enhances sensitivity to hypomethylating agents in myeloid malignancies without impairing normal hematopoiesis, suggesting therapeutic potential through TOPORS inhibition combined with DNA methyltransferase inhibitors. 35 TOPORS mutations cause autosomal dominant retinitis pigmentosa, likely through impaired proteostasis in retinal photoreceptors. 6