Competitive ubiquitination activates the tumor suppressor p53

Xingyao Li, Mengqi Guo, Lun Cai, Tingting Du, Ying Liu, Han Fei Ding, Hongbo Wang, Junran Zhang, Xiaoguang Chen, Chunhong Yan

Research output: Contribution to journalArticle

Abstract

Blocking p53 ubiquitination through disrupting its interaction with MDM2 or inhibiting the MDM2 catalytic activity is the central mechanism by which the tumor suppressor p53 is activated in response to genotoxic challenges. Although MDM2 is first characterized as the major E3 ubiquitin ligase for p53, it can also catalyze the conjugation of ubiquitin moieties to other proteins (e.g., activating transcription factor 3, or ATF3). Here we report that ATF3 can act as an ubiquitin “trap” and competes with p53 for MDM2-mediated ubiquitination. While ATF3-mediated p53 stabilization required ATF3 binding to the MDM2 RING domain, we demonstrated that ATF3 ubiquitination catalyzed by MDM2 was indispensable for p53 activation in response to DNA damage. Moreover, a cancer-derived ATF3 mutant (R88G) devoid of ubiquitination failed to prevent p53 from MDM2-mediated degradation and thus was unable to activate the tumor suppressor. Therefore, we have identified a previously-unknown mechanism that can activate p53 in the genotoxic response.

Original languageEnglish (US)
JournalCell Death and Differentiation
DOIs
StateAccepted/In press - Jan 1 2019

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Ubiquitination
Ubiquitin
Neoplasms
Activating Transcription Factor 3
Ubiquitin-Protein Ligases
DNA Damage
Proteins

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Competitive ubiquitination activates the tumor suppressor p53. / Li, Xingyao; Guo, Mengqi; Cai, Lun; Du, Tingting; Liu, Ying; Ding, Han Fei; Wang, Hongbo; Zhang, Junran; Chen, Xiaoguang; Yan, Chunhong.

In: Cell Death and Differentiation, 01.01.2019.

Research output: Contribution to journalArticle

Li, Xingyao ; Guo, Mengqi ; Cai, Lun ; Du, Tingting ; Liu, Ying ; Ding, Han Fei ; Wang, Hongbo ; Zhang, Junran ; Chen, Xiaoguang ; Yan, Chunhong. / Competitive ubiquitination activates the tumor suppressor p53. In: Cell Death and Differentiation. 2019.
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AU - Liu, Ying

AU - Ding, Han Fei

AU - Wang, Hongbo

AU - Zhang, Junran

AU - Chen, Xiaoguang

AU - Yan, Chunhong

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