ADAR1 downregulation by autophagy drives senescence independently of RNA editing by enhancing p16INK4a levels

Xue Hao, Yusuke Shiromoto, Masayuki Sakurai, Martina Towers, Qiang Zhang, Shuai Wu, Aaron Havas, Lu Wang, Shelley Berger, Peter D. Adams, Bin Tian, Kazuko Nishikura, Andrew V. Kossenkov, Pingyu Liu, Rugang Zhang

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

Abstract

Cellular senescence plays a causal role in ageing and, in mice, depletion of p16INK4a-expressing senescent cells delays ageing-associated disorders1,2. Adenosine deaminases acting on RNA (ADARs) are RNA-editing enzymes that are also implicated as important regulators of human ageing, and ADAR inactivation causes age-associated pathologies such as neurodegeneration in model organisms3,4. However, the role, if any, of ADARs in cellular senescence is unknown. Here we show that ADAR1 is post-transcriptionally downregulated by autophagic degradation to promote senescence through p16INK4a upregulation. The ADAR1 downregulation is sufficient to drive senescence in both in vitro and in vivo models. Senescence induced by ADAR1 downregulation is p16INK4a-dependent and independent of its RNA-editing function. Mechanistically, ADAR1 promotes SIRT1 expression by affecting its RNA stability through HuR, an RNA-binding protein that increases the half-life and steady-state levels of its target mRNAs. SIRT1 in turn antagonizes translation of mRNA encoding p16INK4a. Hence, downregulation of ADAR1 and SIRT1 mediates p16INK4a upregulation by enhancing its mRNA translation. Finally, Adar1 is downregulated during ageing of mouse tissues such as brain, ovary and intestine, and Adar1 expression correlates with Sirt1 expression in these tissues in mice. Together, our study reveals an RNA-editing-independent role for ADAR1 in the regulation of senescence by post-transcriptionally controlling p16INK4a expression.

Original languageEnglish (US)
Pages (from-to)1202-1210
Number of pages9
JournalNature Cell Biology
Volume24
Issue number8
DOIs
StatePublished - Aug 2022
Externally publishedYes

ASJC Scopus subject areas

  • Cell Biology

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