Senescent cells limit p53 activity via multiple mechanisms to remain viable

• DOI: 10.1038/s41467-022-31239-x
• Publication Date: 2022-06-28T17:34:51Z
• Authors: Ines Sturmlechner; Chance C. Sine; Karthik B. Jegana...; Cheng Zhang; Raul O. Fierro Ve...; Darren J. Baker; Hu Li; Jan M. van Deursen
• Keywords: Mice; 0303 health sciences; 03 medical and health sciences; Science; Q; Animals; Apoptosis; Fibroblasts; Tumor Suppressor Protein p53; Article; Cellular Senescence; DNA Damage

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