RNA-catalyzed RNA methylation


Using O6-methylguanine (m6G) as methyl group donor, we recently discovered the first methyl­transferase ribozyme (MTR1), which catalyzes a site-specific intermolecular methyl transfer reaction to generate the native methylated nucleotide 1-methyladenosine m1A. Surprisingly, the structure revealed a cofactor binding site reminiscent of natural purine riboswitches. We found that the catalytic mechanism involves specific nucleobase protonation, and discovered a synergistic effect of two methylated ribose residues in the active site, suggesting that modified nucleotides may have enhanced early RNA catalysis.


Publications on this topic:

C.P.M. Scheitl, M. Ghaem Maghami, A.-K. Lenz, C. Höbartner
Site-specific RNA methylation by a methyltransferase ribozyme
Nature 2020, 587, 663–667

C.P.M. Scheitl, M. Mieczkowski, H. Schindelin, C. Höbartner
Structure and mechanism of the methyltransferase ribozyme MTR1
Nat. Chem. Biol. 2022

RNA-catalyzed RNA labeling


Inspired by natural guide RNAs, which direct protein enzymes sequence-specifically to their targets by Watson-Crick base pairing, we developed ribozymes that covalently ligate bioorthogonal nucleotides to the 2’-OH group of a target nucleotide flanked by the Watson-Crick binding arms. We have shown that suitably derivatized antiviral nucleoside analogues can be repurposed as ribozyme substrates and allow site-specific labelling in the context of total cellular RNA.



Publications on this topic:

M. Ghaem Maghami, C.P.M. Scheitl, C. Höbartner,Direct in vitro selection of trans-acting ribozymes for posttranscriptional, site-specific, and covalent fluorescent labeling of RNA J. Am. Chem. Soc. 2019, 141, 19546-19549.

M. Ghaem Maghami, S. Dey, A.-K. Lenz, C. Höbartner, Repurposing antiviral drugs for orthogonal RNA‐catalyzed labeling of RNA Angew. Chem. Int. Ed. 2020, 59, 9335–9339. Angew. Chem.  2020, 132, 9421-9425.