1. Academic Validation
  2. UFMylation maintains tumour suppressor p53 stability by antagonizing its ubiquitination

UFMylation maintains tumour suppressor p53 stability by antagonizing its ubiquitination

  • Nat Cell Biol. 2020 Sep;22(9):1056-1063. doi: 10.1038/s41556-020-0559-z.
Jiang Liu  # 1 Di Guan  # 1 Maogong Dong 1 Jingjing Yang 1 Haibin Wei 2 Qian Liang 1 Lizhi Song 1 Lu Xu 1 Junjie Bai 1 Cui Liu 1 Jian Mao 1 Qian Zhang 1 Junzhi Zhou 1 Xiaoying Wu 1 Miao Wang 1 Yu-Sheng Cong 3
Affiliations

Affiliations

  • 1 Key Laboratory of Aging and Cancer Biology of Zhejiang Province, Institute of Aging Research, School of Medicine, Hangzhou Normal University, Hangzhou, China.
  • 2 Institute of Cancer and Basic Medicine, Cancer Hospital of the University of Chinese Academy of Sciences, Zhejiang Cancer Hospital, Hangzhou, China.
  • 3 Key Laboratory of Aging and Cancer Biology of Zhejiang Province, Institute of Aging Research, School of Medicine, Hangzhou Normal University, Hangzhou, China. [email protected].
  • # Contributed equally.
Abstract

p53 is the most intensively studied tumour suppressor1. The regulation of p53 homeostasis is essential for its tumour-suppressive function2,3. Although p53 is regulated by an array of post-translational modifications, both during normal homeostasis and in stress-induced responses2-4, how p53 maintains its homeostasis remains unclear. UFMylation is a recently identified ubiquitin-like modification with essential biological functions5-7. Deficiency in this modification leads to embryonic lethality in mice and disease in humans8-12. 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 UFMylation6,13, 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.

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