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

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.