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^2,3,4, how p53 maintains its homeostasis remains unclear. UFMylation is a recently identified ubiquitin-like modification with essential biological functions^5,6,7. Deficiency in this modification leads to embryonic lethality in mice and disease in humans^8,9,10,11,12. 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.

p53是研究最深入的肿瘤抑制因子¹。p53稳态的调节对于其肿瘤抑制功能^2,3至关重要。尽管p53受一系列翻译后修饰的调控，无论是在正常体内平衡过程中还是在应激诱导的反应[ ^2,3,4]中，p53如何保持其体内稳态仍不清楚。UFMylation是最近发现的泛素样修饰，具有基本的生物学功能^5,6,7。这种修饰的缺乏会导致小鼠的胚胎致死率和人类疾病^8,9,10,11,12。在这里，我们报告p53可以被UFM1共价修饰，并且该修饰通过拮抗其泛素化和蛋白酶体降解来稳定p53。从机制上讲，UFL1，即UFM1连接酶⁶，与MDM2竞争结合p53以使其稳定。UFL1或DDRGK1，UFMylation的关键调节剂的消耗^6,13，降低p53的稳定性，进而促进细胞生长和肿瘤在体内形成。临床上，在高百分比的肾细胞癌中，UFL1和DDRGK1的表达下调，并与p53水平呈正相关。我们的研究结果表明，UFMylation是维持p53稳定性和肿瘤抑制功能的重要翻译后修饰，并指出UFMylation是有望成为癌症的治疗靶标。