The tumour suppressor RASSF1A promotes MDM2 self-ubiquitination by disrupting the MDM2-DAXX-HAUSP complex.
The tumour suppressor p53, which accumulates in response to DNA damage and induces cell-cycle arrest and apoptosis, has a key function in the maintenance of genome integrity. Under normal conditions, the antiproliferative effects of p53 are inhibited by MDM2, a ubiquitin ligase that promotes p53 ubiquitination and degradation. MDM2 is also self-ubiquitinated and degraded. Here, we show that the tumour suppressor RASSF1A regulates G(1)-S cell-cycle progression in a p53-dependent manner by promoting MDM2 self-ubiquitination and preventing p53 degradation. Importantly, RASSF1A associates with MDM2 and death-domain-associated protein (DAXX) in the nucleus, thereby disrupting the interactions between MDM2, DAXX, and the deubiquitinase, HAUSP, and enhancing the self-ubiquitin ligase activity of MDM2. Moreover, RASSF1A partially contributes to p53-dependent checkpoint activation at early time points in response to DNA damage. These findings reveal a new and important function for RASSF1A in regulating the p53-MDM2 pathway.
National Research Laboratory for Genomic Stability, Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea.
Min Sup
MS
Song
Su Jung
SJ
Song
So Yeon
SY
Kim
Hyun Jung
HJ
Oh
Dae-Sik
DS
Lim
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D045744:Cell Line, Tumor; D056970:Co-Repressor Proteins; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D051379:Mice; D018832:Molecular Chaperones; D009687:Nuclear Proteins / Q000378:metabolism*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D043222:Ubiquitin Thiolesterase / Q000378:metabolism*; D000076084:Ubiquitin-Specific Peptidase 7; D054875:Ubiquitination
D048868:Adaptor Proteins, Signal Transducing; D056970:Co-Repressor Proteins; C106985:DAXX protein, human; D018832:Molecular Chaperones; D009687:Nuclear Proteins; C411762:RASSF1 protein, human; D025521:Tumor Suppressor Proteins; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; C464569:USP7 protein, human; D043222:Ubiquitin Thiolesterase; D000076084:Ubiquitin-Specific Peptidase 7