Mechanisms and Targeting of RNA Methyltransferases in Cancer and Viral Pathogenesis

N6-methyladenosine (m6A) is the most prevalent internal modification of human mRNAs. The core methyltransferase complex METTL3/METTL14 deposits the majority of these marks and, in a context-dependent manner, dictates transcript fate. Elevated METTL3 activity sustains the leukemic state in acute myeloid leukemia (AML), making this enzyme an attractive therapeutic target. I will present our work on METTL3/METTL14 that advances understanding of its evolution, substrate specificity, and catalytic mechanism. I will also discuss mechanistic crosstalk between protein and RNA/DNA methyltransferases, highlighting a regulatory axis with therapeutic potential.

In the second part of the talk, I will turn to 2′-O-ribose methylation (2′-O-Me), an RNA modification exploited by viruses to promote replication and evade host innate immunity. I will present our structural and biochemical studies of the SARS-CoV-2 Nsp16/Nsp10 methyltransferase, aimed at defining its operating principles, substrate specificity, and mechanism-based inhibition to enable the development of novel antivirals.