RNF4 (ring finger protein 4) is a SUMO-targeted ubiquitin ligase (STUbL) that recognizes polysumoylated proteins and catalyzes their polyubiquitination for proteasomal degradation 1. As a mammalian STUbL, RNF4 mediates Lys-6-, Lys-11-, Lys-48-, and Lys-63-linked polyubiquitination of sumoylated substrates 1. RNF4 regulates critical cellular processes including DNA replication, where it facilitates replication fork stability and ATR-CHK1 signaling by maintaining proper accumulation of Fanconi anemia proteins and helicases at replication forks 2. In response to PARP1 trapping on chr4, RNF4 ubiquitinates sumoylated PARP1, promoting its removal by the p97/VCP ATPase—a process relevant to PARP inhibitor efficacy in cancer therapy 3. RNF4 functions in stress responses, including arsenic-induced PML body degradation and hypoxia responses 1, and works with the related STUbL TOPORS in complementary fashion to clear sumoylated proteins from chr4 4. RNF4 expression is elevated in multiple human tumor types and supports Myc-driven tumorigenesis by enabling DNA replication 2, positioning RNF4 as a potential therapeutic target in cancer, particularly in c-myc-expressing tumors 2.