Repression of p53 function by SIRT5-mediated desuccinylation at Lysine 120 in response to DNA damage

Cell Death Differ. 2022 Apr;29(4):722-736. doi: 10.1038/s41418-021-00886-w. Epub 2021 Oct 12.

Abstract

p53 is a classic tumor suppressor that functions in maintaining genome stability by inducing either cell arrest for damage repair or cell apoptosis to eliminate damaged cells in response to different types of stress. Posttranslational modifications (PTMs) of p53 are thought to be the most effective way for modulating of p53 activation. Here, we show that SIRT5 interacts with p53 and suppresses its transcriptional activity. Using mass spectrometric analysis, we identify a previously unknown PTM of p53, namely, succinylation of p53 at Lysine 120 (K120). SIRT5 mediates desuccinylation of p53 at K120, resulting in the suppression of p53 activation. Moreover, using double knockout mice (p53-/-Sirt5-/-), we validate that the suppression of p53 target gene expression and cell apoptosis upon DNA damage is dependent on cellular p53. Our study identifies a novel PTM of p53 that regulates its activation as well as reveals a new target of SIRT5 acting as a desuccinylase.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • DNA Damage
  • Lysine* / metabolism
  • Mice
  • Mice, Knockout
  • Protein Processing, Post-Translational*
  • Sirtuins* / genetics
  • Sirtuins* / metabolism
  • Tumor Suppressor Protein p53* / genetics
  • Tumor Suppressor Protein p53* / metabolism

Substances

  • SIRT5 protein, mouse
  • Trp53 protein, mouse
  • Tumor Suppressor Protein p53
  • Sirtuins
  • Lysine