Small molecule-based detection of non-canonical RNA G-quadruplex structures that modulate protein translation

Tandem repeats of guanine-rich sequences in RNA often form thermodynamically stable four-stranded RNA structures. Such RNA G-quadruplexes have long been considered to be linked to essential biological processes, yet their physiological significance in cells remains unclear. Here, we report a approach that permits the detection of RNA G-quadruplex structures that modulate protein translation in mammalian cells. The approach combines antibody arrays and RGB-1, a small molecule that selectively stabilizes RNA G-quadruplex structures. Analysis of the protein and mRNA products of 84 cancer-related human genes identified Nectin-4 and CapG as G-quadruplex-controlled genes whose mRNAs harbor non-canonical G-quadruplex structures on their 5 ' UTR region. Further investigations revealed that the RNA G-quadruplex of CapG exhibits a structural polymorphism, suggesting a possible mechanism that ensures the translation repression in a KCl concentration range of 25-100 mM. The approach described in the present study sets the stage for further discoveries of RNA G-quadruplexes.

Automated summary

In this study, a new method was developed to detect RNA G-quadruplex structures that regulate protein translation in mammalian cells. By analyzing the products of cancer-related genes, two genes controlled by RNA G-quadruplexes were identified, with non-canonical G-quadruplex structures in their mRNA. Further investigation revealed that the RNA G-quadruplex showed structural polymorphism, potentially ensuring translation repression under certain conditions.