To protect and modify double-stranded RNA – the critical roles of ADARs in development, immunity and oncogenesis

Abstract

Adenosine deaminases that act on RNA (ADARs) are present in all animals and function to both bind double-stranded RNA (dsRNA) and catalyze the deamination of adenosine (A) to inosine (I). As inosine is a biological mimic of guanosine, deamination by ADARs changes the genetic information in the RNA sequence and is commonly referred to as RNA editing. Millions of A-to-I editing events have been reported for metazoan transcriptomes, indicating that RNA editing is a widespread mechanism used to generate molecular and phenotypic diversity. Loss of ADARs results in lethality in mice and behavioral phenotypes in worm and fly model systems. Furthermore, alterations in RNA editing occur in over 35 human pathologies, including several neurological disorders, metabolic diseases, and cancers. In this review, a basic introduction to ADAR structure and target recognition will be provided before summarizing how ADARs affect the fate of cellular RNAs and how researchers are using this knowledge to engineer ADARs for personalized medicine. In addition, we will highlight the important roles of ADARs and RNA editing in innate immunity and cancer biology.

Graphical Abstract

Keywords:

• Double-stranded RNA (dsRNA)
• ADAR
• RNA editing
• inosine
• dsRBP
• cancer
• innate immunity
• RNA modification

Acknowledgements

The authors thank Suba Rajendren and Reshma Kurup for comments on the initial manuscript and the four anonymous referees for excellent suggestions on improving the review. Some illustrations were created with BioRender.com.

Disclosure statement

No potential conflict of interest was reported by the author(s). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Additional information

Funding

Work in the Hundley lab is supported by the National Science Foundation (Award Number 1917050) and the National Institutes of Health/National Institute of General Medical Sciences [R01GM130759]. Emily Erdmann is supported by the Graduate Training Program in Quantitative and Chemical Biology National Institutes of Health/National Institute of General Medical Sciences [T32 GM131994] and Indiana University.