Riboswitches

Abstract

Riboswitches are mRNA domains that regulate gene expression in cis in response to the intracellular concentration of small molecules. In bacteria, they control gene expression during transcription and translation. One bacterial riboswitch that is a small molecule-activated self-cleaving RNA (i.e., a ribozyme) that induces mRNA decay in cis, is known. Eukaryal riboswitches that regulate alternative splicing and polyadenylation have been described. Riboswitches are a common gene regulation strategy in Gram-positive bacteria, where they are associated with >5% of genes. Formally, most riboswitches can be divided into two domains. The “aptamer domain” is responsible for recognition of the effector small molecule. The sequence of this domain is highly conserved across phylogeny. The highly variable “expression platform” interfaces with the transcription, translation, or splicing machineries. Aptamer domains have been discovered that recognize a wide range of metabolites including purines, the amino acids glycine, asparagine and lysine, the modified sugar glucosamine-6-phosphate, the coenzymes adenosylcobalamin, flavin mononucleotide (FMN), tetrahydrofolate (THF), thiamine pyrophosphate (TPP), and S-adenosylmethionine (SAM), simple ions (Cd2+, Co2+, F−, Mg2+, Mn2+, Ni2+), as well as the second messengers cyclic diadenylate (c-di-AMP) and cyclic diguanylate (c-di-GMP). Riboswitches showcase the ability of RNA to recognize small molecules with high affinity and specificity. Their prevalence in bacteria and their ability to bind small molecules makes them attractive targets for the development of new antibiotics, and their modularity has been exploited for synthetic biology applications.