Senescent cells limit p53 activity via multiple mechanisms to remain viable

Ines Sturmlechner, Chance C. Sine, Karthik B. Jeganathan, Cheng Zhang, Raul O. Fierro Velasco, Darren J. Baker, Hu Li, Jan M. van Deursen

Research output: Contribution to journalArticlepeer-review

Abstract

Super-enhancers regulate genes with important functions in processes that are cell type-specific or define cell identity. Mouse embryonic fibroblasts establish 40 senescence-associated super-enhancers regardless of how they become senescent, with 50 activated genes located in the vicinity of these enhancers. Here we show, through gene knockdown and analysis of three core biological properties of senescent cells that a relatively large number of senescence-associated super-enhancer-regulated genes promote survival of senescent mouse embryonic fibroblasts. Of these, Mdm2, Rnase4, and Ang act by suppressing p53-mediated apoptosis through various mechanisms that are also engaged in response to DNA damage. MDM2 and RNASE4 transcription is also elevated in human senescent fibroblasts to restrain p53 and promote survival. These insights identify key survival mechanisms of senescent cells and provide molecular entry points for the development of targeted therapeutics that eliminate senescent cells at sites of pathology.

Original languageEnglish (US)
Article number3722
JournalNature communications
Volume13
Issue number1
DOIs
StatePublished - Dec 2022

ASJC Scopus subject areas

  • General Chemistry
  • General Biochemistry, Genetics and Molecular Biology
  • General Physics and Astronomy

Fingerprint

Dive into the research topics of 'Senescent cells limit p53 activity via multiple mechanisms to remain viable'. Together they form a unique fingerprint.

Cite this