Unraveling the structure and biological functions of RNA triple helices

It has been nearly 63 years since the first characterization of an RNA triple helix in vitro by Gary Felsenfeld, David Davies, and Alexander Rich. An RNA triple helix consists of three strands: A Watson–Crick RNA double helix whose major‐groove establishes hydrogen bonds with the so‐called “third strand”. In the past 15 years, it has been recognized that these major‐groove RNA triple helices, like single‐stranded and double‐stranded RNA, also mediate prominent biological roles inside cells. Thus far, these triple helices are known to mediate catalysis during telomere synthesis and RNA splicing, bind to ligands and ions so that metabolite‐sensing riboswitches can regulate gene expression, and provide a clever strategy to protect the 3′ end of RNA from degradation. Because RNA triple helices play important roles in biology, there is a renewed interest in better understanding the fundamental properties of RNA triple helices and developing methods for their high‐throughput discovery. This review provides an overview of the fundamental biochemical and structural properties of major‐groove RNA triple helices, summarizes the structure and function of naturally occurring RNA triple helices, and describes prospective strategies to isolate RNA triple helices as a means to establish the “triplexome”. This article is categorized under: RNA Structure and Dynamics > RNA Structure and Dynamics. RNA Structure and Dynamics > RNA Structure, Dynamics and Chemistry. RNA Structure and Dynamics > Influence of RNA Structure in Biological Systems.