Endonuclease V: From Transcriptome Regulator to Chemical Biology Tool

Posttranscriptional modifications play a pivotal role in regulating the health and physiology of human cells and adenosine-to-inosine (A-to-I) editing is one of the most abundant of these modifications. Inosine is read as guanosine by the cellular machinery and this change impacts both the regulation and genetic code of RNA, in turn effectively rewiring both the transcriptome and proteome. Given these crucial functions, it is not surprising that A-to-I editing is implicated in a number of disease processes, including cancers and neurological disorders. While ADARs have been identified as the primary writers for inosine modification, putative readers and erasers have received far less attention. Recent studies have revealed that the Endonuclease V (EndoV) family of enzymes has the unique ability to detect and cleave inosine-containing RNAs, suggesting that EndoV may regulate the fate of edited RNAs in the cell. Despite this potentially important role, human Endonuclease V (hEndoV) remains relatively understudied, and in some cases, conflicting results have been presented regarding the activity of hEndoV. Here, we aim to bring together this existing knowledge in order to further spur investigation into this potentially crucial regulator of A-to-I editing. We first describe biochemical and structural studies that reveal the molecular aspects of inosine recognition and RNA cleavage, and the evolution of these functions from DNA repair in prokaryotes to RNA cleavage in eukaryotes. Based upon this knowledge, we discuss reports suggesting the role of hEndoV in human physiology. Finally, we highlight technologies that leverage EndoV for mapping and quantifying A-to-I editing <i>in vitro</i> and in cells and tissues.