SAG E3 Ubiquitin Ligase: Biological Functions, Mechanism of Action and Associated Human Diseases

YU Qing¹, SUN Yi^2,3,4,5*

(¹Department of Thyroid Surgery, the Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou 310022, China; ²Cancer Institute of the Second Affiliated Hospital, Hangzhou 310029, China; ³Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou 310029, China; ⁴Cancer Center, Zhejiang University, Hangzhou 310058, China; ⁵Research Center for Life Science and Human Health, Binjiang Institute of Zhejiang University, Hangzhou 310053, China)

Abstract:

SAG (Sensitive to Apoptosis Gene) is an evolutionarily conserved RING finger protein, firstly cloned in 1997 in the author's laboratory and published in 1999. Numerous studies have demonstrated that SAG is not only an antioxidant protein that protects cells from apoptosis induced by metal ion or ROS, but also an important RING component of Cullin-RING ligases with oncogenic property, and being validated as an attractive anticancer target. SAG acts as an E3 ligase for both neddylation and ubiquitylation. Via neddylating Cullin-5, SAG activates CRL5, and then complexes with other components of CRL5 or CRL1 to promote ubiquitylation and degradation of many tumor suppressive substrates, leading to enhanced proliferation, survival, angiogenesis, and tumorigenesis. In addition, SAG is also involved in virus infection and associated with a few other human diseases. The drug discovery effort is currently under the way to identify small molecule inhibitors of SAG for anti-cancer applications. This review summarizes current knowledge and advancement in the field of SAG research, including its protein structure, biochemical activities, biological functions, especially in tumorigenesis, and mechanisms of action. Finally, the future perspectives in the basic research of SAG and SAG-targeting drug discovery efforts are proposed.

CSTR: 32200.14.cjcb.2022.04.0012