Article
- The EMBO Journal (2008) 27, 1863 - 1874
- doi:10.1038/emboj.2008.115
Published online: 19 June 2008
Subject Categories:
The tumour suppressor RASSF1A promotes MDM2 self-ubiquitination by disrupting the MDM2–DAXX–HAUSP complex
Min Sup Song1,a, Su Jung Song1,a, So Yeon Kim1, Hyun Jung Oh1 and Dae-Sik Lim1
- National Research Laboratory for Genomic Stability, Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea
Correspondence to:
Dae-Sik Lim, Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), 373-1 Guseoung-D, Yuseong-G, Daejeon 305-701, Republic of Korea. Tel.: +82 42 869 2635; Fax: +82 42 869 2610; E-mail: daesiklim@kaist.ac.kr
aThese authors contributed equally to this work
Received 14 December 2007; Accepted 20 May 2008
Abstract
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 G1–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.
Keywords:
- DAXX,
- MDM2,
- p53,
- RASSF1A
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