USP22 antagonizes p53 transcriptional activation by deubiquitinating Sirt1 to suppress cell apoptosis and is required for mouse embryonic development

Mol Cell. 2012 May 25;46(4):484-94. doi: 10.1016/j.molcel.2012.03.024. Epub 2012 Apr 26.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / genetics
  • Apoptosis / physiology
  • DNA Damage
  • Embryonic Development / genetics
  • Embryonic Development / physiology*
  • Endopeptidases / deficiency
  • Endopeptidases / genetics
  • Endopeptidases / metabolism*
  • Enzyme Stability
  • Female
  • HEK293 Cells
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Pregnancy
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Sirtuin 1 / genetics
  • Sirtuin 1 / metabolism*
  • Transcriptional Activation
  • Tumor Suppressor Protein p53 / metabolism*
  • Ubiquitin-Specific Proteases
  • Ubiquitination

Substances

  • Recombinant Proteins
  • Tumor Suppressor Protein p53
  • Endopeptidases
  • Ubiquitin-Specific Proteases
  • Sirt1 protein, mouse
  • Sirtuin 1