Sprecher
Beschreibung
Takumi Okuda, Claudia Höbartner*
A variety of RNA modifications, collectively known as epitranscriptome, have been discovered across all classes of RNA, with over 150 distinct types identified in modern organisms. Among these modifications, methylation is the most abundant and simplest modification, carried out by enzymes using the ubiquitous methyl donor S-adenosylmethionine (SAM). In ribosomes,ancient molecular fossils of naturally occurring ribozymes, multiple methylations have been shown to improve translational accuracy and efficiency. Similarly, in synthetic ribozymes, site-specific methylation of the catalytic core has been demonstrated to dramatically boost their catalytic activity [1]. These examples underscore that RNA modification provides a plausible explanation for how RNA has enhanced their functionality in RNA world. To explore this concept, we examined the possibility of RNA-catalyzed RNA modification and successfully discovered SAM-dependent methyltransferase ribozymes that mimic the methylation mechanism of modern organisms [2]. The target ribozyme was evolved from a chemically synthesized library of 1015 different RNA sequences using a propargylic cofactor ProSeDMA, which mimics the SAM structure with four atomic mutations and transfers a “clickable” tag. Our selection strategy revealed a ribozyme that transfers the click-tag and we subsequently screened for candidates that also tolerate natural SAM. Active sequences were selectively enriched after click reaction, leading to the discovery of a new ribozyme named SAMURI (SAM analogue Utilizing Ribozyme). SAMURI exhibited high catalytic activity for selective transfer of click tags to target RNA and also accepted native SAM as a cofactor. The crystal structure of SAMURI was solved at a resolution of 2.9 Å after multiple optimizations of sequence constructs [3]. The structure revealed a unique architecture of the catalytic core that consisted of four individual layers orienting the transferred alkyl group in front of the target adenosine. These findings demonstrate that RNA-catalyzed RNA methylation could have occurred in the RNA world, potentially using SAM in a manner reminiscent of the modern epitranscriptome.
References: [1] C.P.M. Scheitl, C. Höbartner et al. Nat Chem Biol., 2022, 18, 547-555. [2] Okuda, T., Lenz, A.K., Seitz, F., Vogel, J., Höbartner, C. Nat. Chem., 2023, 15, 1523-1531. [3] Chen, H-A., Okuda, T., Lenz, A.K., Scheitl, C.P.M., Schindelin, H., Höbartner, C. Nat Chem Biol., 2025, doi:10.1038/s41589-024-01808-w
