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 and Jan M. Deursen ()
Additional contact information
Ines Sturmlechner: Mayo Clinic
Chance C. Sine: Mayo Clinic
Karthik B. Jeganathan: Mayo Clinic
Cheng Zhang: Mayo Clinic
Raul O. Fierro Velasco: Mayo Clinic
Darren J. Baker: Mayo Clinic
Hu Li: Mayo Clinic
Jan M. Deursen: Mayo Clinic

Nature Communications, 2022, vol. 13, issue 1, 1-14

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-31239-x

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