Phototriggered Morphological and Compositional Change of UGGAA Repeat RNA Foci by Photoswitchable RNA‐Binding Ligand

Abstract

ABSTRACT The expansion of specific repeat sequences causes dozens of heritable neuromuscular diseases, where expanded repeat RNAs play key roles in the pathogenic mechanism. Although the formation of RNA foci has been identified as a common hallmark of repeat diseases, their properties, dynamics, and mechanisms underlying toxicity remain elusive. Here, we demonstrate a novel strategy for the optical control of UGGAA repeat RNA foci, a pathological hallmark of spinocerebellar ataxia type 31 (SCA31), based on the modulation of RNA–RNA interactions by a photoswitchable RNA‐binding ligand, NCTA. In the presence of NCTA, UV irradiation induced the growth of UGGAA repeat RNA foci in cells. Subsequent visible light irradiation dissolved the structure into the original smaller RNA foci. Reversible photoisomerization between E ‐ and Z ‐NCTA is responsible for the photocontrol of RNA foci, where Z‐NCTA stabilizes the association between UGGAAs. These changes were accompanied by alterations in the composition of RNA‐binding proteins within the RNA foci, suggesting that NCTA modulates their properties and functions by remodeling RNA foci. Our photocontrol system will be useful for investigating, manipulating and regulating dynamic structures containing RNA scaffolds, including disease‐related repeat RNA foci and membraneless ribonucleoprotein organelles.