Our genetic code is linked to the cellular workforce, proteins, through the interplay of three nucleic acids: mRNA, tRNA and rRNA. All 3 RNAs are substantially modified and the insertion of the correct modification can be inhibited by pharmaceutical drugs. E.g. drugs called antimetabolites are molecules that mimick nucleobases or nucleos/tide structures and they are used in e.g. cancer therapy and as antimicrobial antibiotics. Yet, only little is known how antimetabolites impact the human epitranscriptome.
Antimetabolites
Within the CRC1309, we studied the incorporation of azacytidine into tRNA and we found a substantial decrease in 5-methylcytidine ([1] work done with the Traube lab).
Inspired by this finding, we studied 5-fluoruracil, a common anticancer drug (12 Mio DDD/2023) which is also known to inhibit enzymes responsible for pseudouridine and 5-methyluridine formation in tRNA. Indeed, we find a loss of both modifications in tRNA, but in rRNA, we also find a loss of pseudouridine. Importantly, under temporal resolution using NAIL-MS, we see various other RNA modifications deviating in their abundance under 5-FU treatment. All in all, we proved the hypothesized hypomodification of rRNA and tRNA under 5-FU treatment, which is currently viewed as the main driver of 5-FU-induced lethality [2].
Together with the Blango lab, we studied 5-Fluorcytosine in the pathogen A. fumigatus and we found an inetrdependance of 5-FU toxicity and the tRNA modification i6A. This is an important aspect when considering antibiotic regimes for infection [3].
Non-antimetabolite structured drugs
Work in progress.
