Scientists Reveal New Function of Enzyme ADAR1 Linking it to Age-Related Diseases

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"... revealed a novel ADAR1-SIRT1-p16INK4a axis in regulating cellular senescence and its potential implications in tissue aging. ...
Central to this quest is a protein called p16INK4a because its expression both increases during tissue aging and it drives senescence Prior studies established that depletion of p16INK4a expressing cells is sufficient to delay age-associated disorders. ...
showed that stressed cells utilize ADAR1 as protection from apoptosis, programmed cell death ...
discovered that ADAR1 loss promotes p16INK4a expression through SIRT1, another protein known to regulate both senescence and tissue aging. Interestingly, this function of ADAR1 does not depend on its biological role in RNA editing. ...
downregulation of ADAR1 by a process called autophagy (the degradation and recycling of damaged or unneeded cell components) during senescence decreased the stability of SIRT1 mRNA, which in turn upregulated the translation of p16INK4a to induce senescence. ..."

From the abstract:

"Cellular senescence plays a causal role in ageing and, in mice, depletion of p16INK4a-expressing senescent cells delays ageing-associated disorders. 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 organisms. 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."

Wistar Scientists Reveal New Function of Enzyme ADAR1 Linking it to Age-Related Diseases via a Role Independent of RNA-editing During Aging

ADAR1 downregulation by autophagy drives senescence independently of RNA editing by enhancing p16INK4a levels (no public access)