USP22 Antagonizes p53 Transcriptional Activation by Deubiquitinating Sirt1 to Suppress Cell Apoptosis and Is Required for Mouse Embryonic Development

Zhenghong Lin, Heeyoung Yang, Qingfei Kong, Jinping Li, Sang Myeong Lee, Beixue Gao, Hongxin Dong, Jianjun Wei, Jianxun Song, Donna Zhang, Deyu Fang

Research output: Contribution to journalArticle

135 Citations (Scopus)

Abstract

The NAD-dependent histone deacetylase Sirt1 antagonizes p53 transcriptional activity to regulate cell-cycle progression and apoptosis. We have identified a ubiquitin-specific peptidase, USP22, one of the 11 death-from-cancer signature genes that are critical in controlling cell growth and death, as a positive regulator of Sirt1. USP22 interacts with and stabilizes Sirt1 by removing polyubiquitin chains conjugated onto Sirt1. The USP22-mediated stabilization of Sirt1 leads to decreasing levels of p53 acetylation and suppression of p53-mediated functions. In contrast, depletion of endogenous USP22 by RNA interference destabilizes Sirt1, inhibits Sirt1-mediated deacetylation of p53 and elevates p53-dependent apoptosis. Genetic deletion of the usp22 gene results in Sirt1 instability, elevated p53 transcriptional activity and early embryonic lethality in mice. Our study elucidates a molecular mechanism in suppression of cell apoptosis by stabilizing Sirt1 in response to DNA damage and reveals a critical physiological function of USP22 in mouse embryonic development.

Original languageEnglish (US)
Pages (from-to)484-494
Number of pages11
JournalMolecular Cell
Volume46
Issue number4
DOIs
StatePublished - May 25 2012

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Transcriptional Activation
Embryonic Development
Apoptosis
Polyubiquitin
Histone Deacetylases
Neoplasm Genes
Gene Deletion
Acetylation
Ubiquitin
RNA Interference
NAD
DNA Damage
Cell Cycle
Peptide Hydrolases
Cell Death
Growth

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

USP22 Antagonizes p53 Transcriptional Activation by Deubiquitinating Sirt1 to Suppress Cell Apoptosis and Is Required for Mouse Embryonic Development. / Lin, Zhenghong; Yang, Heeyoung; Kong, Qingfei; Li, Jinping; Lee, Sang Myeong; Gao, Beixue; Dong, Hongxin; Wei, Jianjun; Song, Jianxun; Zhang, Donna; Fang, Deyu.

In: Molecular Cell, Vol. 46, No. 4, 25.05.2012, p. 484-494.

Research output: Contribution to journalArticle

Lin, Zhenghong ; Yang, Heeyoung ; Kong, Qingfei ; Li, Jinping ; Lee, Sang Myeong ; Gao, Beixue ; Dong, Hongxin ; Wei, Jianjun ; Song, Jianxun ; Zhang, Donna ; Fang, Deyu. / USP22 Antagonizes p53 Transcriptional Activation by Deubiquitinating Sirt1 to Suppress Cell Apoptosis and Is Required for Mouse Embryonic Development. In: Molecular Cell. 2012 ; Vol. 46, No. 4. pp. 484-494.
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