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MDM2-mediated degradation of WRN promotes cellular senescence in a p53-independent manner

Oncogene volume 38, pages 2501–2515 (2019)Cite this article

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Abstract

MDM2 (Murine double minute 2) acts as a key repressor for p53-mediated tumor-suppressor functions, which includes cellular senescence. We found that MDM2 can promote cellular senescence by modulating WRN stability. Werner syndrome (WS), caused by mutations of the WRN gene, is an autosomal recessive disease, which is characterized by premature aging. Loss of WRN function induces cellular senescence in human cancer cells. Here, we found that MDM2 acts as an E3 ligase for WRN protein. MDM2 interacts with WRN both in vivo and in vitro. MDM2 induces ubiquitination of WRN and dramatically downregulates the levels of WRN protein in human cells. During DNA damage response, WRN is translocated to the nucleoplasm to facilitate its DNA repair functions; however, it is degraded by the MDM2-mediated ubiquitination pathway. Moreover, the senescent phenotype induced by DNA damage reagents, such as Etoposide, is at least in part mediated by MDM2-dependent WRN degradation as it can be significantly attenuated by ectopic expression of WRN. These results show that MDM2 is critically involved in regulating WRN function via ubiquitin-dependent degradation and reveal an unexpected role of MDM2 in promoting cellular senescence through a p53-independent manner.

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Acknowledgements

We thank Dr. Jiadong Wang for generously providing Lenti-CRISPR-V2 plasmid. HCT116 p53−/− cell is a kind gift from Dr. Xiaojuan Du.

Author contributions

BL and JL designed research; BL, JY, XY, LL, XL, ZZ and JZ performed research; BL, ZW, HQ, W-GZ and JL analyzed data; and BL, WG, and JL wrote the paper.

Funding

This work was supported by National Natural Science Foundation of China (81270427, 81471405, 81671389, 81720108027 and 81321003) and from National Research Program of National Natural Science Foundation of China China (973 Program, 2013CB530801).

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Affiliations

  1. Department of Medical Genetics, Peking University Health Science Center, 38 Xueyuan Road, 100191, Beijing, China

    Boya Liu, Xin Yang, Lu Liu, Xinlin Lou, Zeyuan Zhang, Hao Qi, Zhe Wang, Junhua Zou & Jianyuan Luo

  2. Institute for Cancer Genetics, Columbia University, New York, NY, 10032, USA

    Jingjie Yi & Wei Gu

  3. Department of Biochemistry and Molecular Biology, Shenzhen University School of Medicine, Shenzhen, China

    Wei-Guo Zhu

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  1. Boya Liu
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Correspondence to Jianyuan Luo.

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Liu, B., Yi, J., Yang, X. et al. MDM2-mediated degradation of WRN promotes cellular senescence in a p53-independent manner. Oncogene 38, 2501–2515 (2019). https://doi.org/10.1038/s41388-018-0605-5

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