Home Cellular science Scientists reveal a new function of the ADAR1 enzyme linking it to age-related diseases via an independent role in RNA editing during aging

Scientists reveal a new function of the ADAR1 enzyme linking it to age-related diseases via an independent role in RNA editing during aging

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Aging and age-related disorders pose a complex challenge to the biomedical research community. Better understanding how senescence is regulated is of great importance to promote healthy aging and treat age-associated disorders. In a research article published today in Cell Biology NatureRugang Zhang, Ph.D., Deputy Director of the Ellen and Ronald Caplan Cancer Center, Christopher M. Davis Endowed Professor and Program Leader of the Immunology, Microenvironment & Metastasis Program, Wistar Institute, and his team revealed a novel ADAR1-SIRT1 axis -p16INK4a in the regulation of cellular senescence and its potential implications in tissue aging.

“Understanding the basic mechanism underlying tissue aging is challenging and cellular senescence offers an angle into the complex biology that drives tissue aging. tissues can in turn be used to promote healthy aging and fight age disorders.” says Zhang.

At the heart of this quest is a protein called p16INK4a because its expression both increases during tissue aging and drives senescence. Previous studies have established that depletion of p16INK4a-expressing cells is sufficient to delay age-associated disorders. Thus, approaches that prevent age-associated increases in p16INK4a expression may have important implications in designing intervention strategies to promote healthy aging.

The research team’s findings relate to a protein called ADAR1. ADAR1 is a specialized enzyme involved in RNA editing and is now revealed in senescence. Postdoctoral researcher in the Zhang lab and first author of the paper Xue Hao, Ph.D., explains that this research was largely inspired by previous independent research conducted on model organisms such as fruit flies and worms showing that the Depletion of the human equivalent of ADAR1 in these organisms reduces lifespan and causes age-related changes such as neurodegeneration.

This story also benefits from a highly collaborative culture of the Wistar Institute. In fact, previous work by Kazuko Nishikura, Ph.D., a professor in the Gene Expression and Regulation Program at the Ellen and Ronald Caplan Cancer Center at Wistar—and a pioneer in ADAR1 biology—showed that stressed cells use ADAR1 as protection against apoptosis, programmed cell death. “As senescent cells are stressed and apoptosis-resistant cells, the first question we asked was whether ADAR1 is related to cellular senescence and second, how does it regulate senescence and what is its involvement? potential in tissue aging.” Ha explains.

The team first examined the expression of ADAR1 in vitro in human fibroblasts and in vivo in several tissues from young and old mice. Next, they experimentally altered ADAR1 expression in multiple cell types in petri dish and mouse tissues to establish ADAR1 as a critical regulator of p16INK4a expression. Curiously, the team found that loss of ADAR1 promotes expression of p16INK4a via SIRT1, another protein known to regulate both tissue senescence and aging. Interestingly, this function of ADAR1 does not depend on its biological role in RNA editing.

They also found that down-regulation of ADAR1 through a process called autophagy (the breakdown and recycling of damaged or unnecessary cellular components) during senescence decreased the stability of SIRT1 mRNA, which in turn down-regulated. up-translation of p16INK4a to induce senescence. Hao elaborates: “Our study revealed a novel ADAR1-SIRT1-p16 INK4a axis that plays an important role in cellular senescence at the translational level, and this newly defined function of ADAR1 is independent of its RNA editing function. “

Zhang says, “Our study begins to reveal the missing link between ADAR1 and tissue aging through the expression of p16INK4a during senescence. Additionally, these findings have provided a scientific rationale to explore whether this newly discovered mechanism can be exploited to therapeutic development regarding age-related disorders.”

“One way to potentially restore ADAR1 expression as a means to suppress p16INK4a and the senescence observed during tissue aging is to inhibit autophagy.” Ah details. She adds about the next steps in research: “Our study raises some interesting questions. For example, what is the relative contribution of this mechanism to p16INK4a expression during aging in different tissues? Additionally, it would be of interest to determine whether intervention of this pathway can attenuate age-associated disorders that are linked to p16INK4a expression in previous published animal models.

Co-authors: Xue Hao, Yusuke Shiromoto, Masayuki Sakurai, Martina Towers, Qiang Zhang, Shuai Wu, Bin Tian, ​​Andrew Kossenkov, Kazuko Nishikura, Pingyu Liu from Wistar Institute; Aaron Havas, Peter D. Adams of Sanford Burnham Prebys Medical Discovery Institute; Lu Wang, Shelley Berger of the University of Pennsylvania.

Work supported by: This work was supported by grants from the US National Institutes of Health (R01CA160331 to RZ, P01AG031862 to PDA, SLB and RZ, R01GM040536 and R01GM130716 to KN, and R50CA211199 to AVK). KN was supported by a grant from Emerson Collective. Support for basic facilities was provided by Cancer Center Support Grant (CCSG) CA010815 to the Wistar Institute.