ADAR1 and its implications in cancer development and treatment

The family of adenosine deaminases acting on RNA (ADARs) regulates global gene expression output by catalyzing adenosine-to-inosine (A-to-I) editing of double-stranded RNA (dsRNA) and through interacting with RNA and other proteins. ADARs play important roles in development and disease, including an increasing connection to cancer progression. ADAR1 has demonstrated a largely pro-oncogenic role in a growing list of cancer types, and its function in cancer has been attributed to diverse mechanisms. Here, we review existing literature on ADAR1 biology and function, its roles in human disease including cancer, and summarize known cancer-associated phenotypes and mechanisms. Lastly, we discuss implications and outstanding questions in the field, including strategies for targeting ADAR1 in cancer. The epitranscriptome represents an emerging novel layer of gene regulation that goes awry in cancer. Many RNA-modifying enzymes have been implicated in cancer, including the adenosine-to-inosine (A-to-I) editors called adenosine deaminases acting on RNA (ADARs).ADARs are multifunctional proteins that regulate the transcriptome via A-to-I editing, RNA binding, and direct protein interactions. All of these functions have been implicated in cancer development in diverse tissue contexts. Here, we focus on the predominantly oncogenic role of ADAR1.In addition to mechanisms mediated by a specific target, ADAR1 also regulates interferon signaling via double-stranded RNA (dsRNA) sensors, which translates to an immunosuppressive function in the cancer context. Recently, a role in resolving R loops has been proposed to regulate genome integrity and senescence, and thus another cancer hallmark.