TY - JOUR
T1 - Senescent cells limit p53 activity via multiple mechanisms to remain viable
AU - Sturmlechner, Ines
AU - Sine, Chance C.
AU - Jeganathan, Karthik B.
AU - Zhang, Cheng
AU - Fierro Velasco, Raul O.
AU - Baker, Darren J.
AU - Li, Hu
AU - van Deursen, Jan M.
N1 - Funding Information:
We thank Jeremy T. Stutchman, Ismail Can, Erik-Jan van Deursen, Naomi Hamada, Jan Grasic, Jazeel F. Limzerwala, and Do Young Lim for their help with functional studies, as well as Christian A. Ross, Tamas Ordog, and Jeong-Heon Lee for assistance with the acquisition and interpretation of SE data. We are grateful to Remi-Martin Laberge for advice on survival studies and Marten H. Hofker and Bart van de Sluis for intellectual input. This work was supported by grants from Mayo Clinic’s Center for Biomedical Discovery, the Paul F. Glenn Foundation, the Keck Foundation and the US National Institutes of Health (NIH) grants R01 AG057493, R01 CA096985, and R01 AG56318.
Publisher Copyright:
© 2022, The Author(s).
PY - 2022/12
Y1 - 2022/12
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-022-31239-x
DO - 10.1038/s41467-022-31239-x
M3 - Article
C2 - 35764649
AN - SCOPUS:85132964924
SN - 2041-1723
VL - 13
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 3722
ER -