UFMylation maintains tumour suppressor p53 stability by antagonizing its ubiquitination

Abstract

p53 is the most intensively studied tumour suppressor¹. The regulation of p53 homeostasis is essential for its tumour-suppressive function^2,3. Although p53 is regulated by an array of post-translational modifications, both during normal homeostasis and in stress-induced responses^2-4, how p53 maintains its homeostasis remains unclear. UFMylation is a recently identified ubiquitin-like modification with essential biological functions^5-7. Deficiency in this modification leads to embryonic lethality in mice and disease in humans^8-12. Here, we report that p53 can be covalently modified by UFM1 and that this modification stabilizes p53 by antagonizing its ubiquitination and proteasome degradation. Mechanistically, UFL1, the UFM1 ligase⁶, competes with MDM2 to bind to p53 for its stabilization. Depletion of UFL1 or DDRGK1, the critical regulator of UFMylation^6,13, decreases p53 stability and in turn promotes cell growth and tumour formation in vivo. Clinically, UFL1 and DDRGK1 expression are downregulated and positively correlated with levels of p53 in a high percentage of renal cell carcinomas. Our results identify UFMylation as a crucial post-translational modification for maintenance of p53 stability and tumour-suppressive function, and point to UFMylation as a promising therapeutic target in cancer.