ADARs: pleiotropy in function, versatility in application

Abstract RNA processing is essential for proper cellular function, contributing to protein and cell state diversity, and is often dysregulated in diseased states. A key subset of RNA regulators is the double-stranded RNA-specific adenosine deaminase (ADAR) protein family, which hydrolytically deaminates double-stranded RNA, causing an adenosine-to-inosine edit (A-to-I). Active ubiquitously throughout the body, this pleiotropic protein family plays critical roles in embryonic patterning, neurological function, and immune regulation. Their aberrant activity has in turn been implicated in a spectrum of disorders, including cancer, metabolic diseases, and autoimmune conditions. By instead purposefully modulating their activity, ADARs have been leveraged to create a versatile toolset for transcriptome engineering. This includes enabling programmable RNA editing, controlled RNA splicing, reversibly modulating protein interactions, and altering cellular inflammation. Here, we review the pleiotropic functions and versatile applications of ADARs, as well as outline areas for growth and potential new avenues in both therapeutics and research.