SAG/RBX2/ROC2/RNF7 dual E3 ligase: From target identification, validation to drug discovery

SAG (Sensitive to Apoptosis Gene), also known as RBX2/ROC2/RNF7, was originally cloned as a redox-inducible gene encoding a cysteine-enriched antioxidant protein. SAG was subsequently characterized as the second family member of the RBX with RING domain, essential for E3 ligase activity in both ubiquitylation and neddylation. Data accumulated over the past 26 years have shown that SAG is overexpressed in many types of human cancer tissues with positive correlation of poor patient survival. Functional studies have revealed that SAG is essential for cancer cell growth, and for tumorigenesis induced by oncogene activation and tumor suppressor inactivation in several genetically modified mouse models. Mechanistically, SAG acts as a catalytic subunit of CRL5 as well as CRL1 to ubiquitylate and degrade mainly tumor suppressor substrates, whereas SAG knockdown or knockout causes their accumulation to inhibit the growth and survival of cancer cells, and tumor progression. Thus, SAG E3 is emerging as an attractive anti-cancer target with drug discovery of small molecule inhibitors and PROTAC degraders being currently pursued. Here, we provide a comprehensive literature review on SAG, from its molecular cloning, biochemical activities, and biological function, to SAG validation as an anti-cancer target, and finally to the drug discovery efforts of SAG targeting agents. The perspectives are also proposed for current challenges and future directions on the study of SAG-associated neddylation-CRLs.