Abstract

Many modifications are known to exist on tRNA and rRNA but very few have been detected on mRNA and ncRNA. We assume that this imbalance is due to the lower abundance and complexity of the latter and therefore an issue of detection. We have therefore developed sensitive tools for the detection of modifications on mRNA and ncRNA including, mass –spec technology, antibodies and chemical reactivity assays. We have also defined an atlas of RNA modifying enzymes required for the viability of AML -leukaemia cells using CRISPR approaches.

Using these tools we are now investigating the biological function, mechanism of action and cancer connection of several RNA modifications. We have shown that the METTL3 enzyme, that modifies m6A, is necessary for AML -leukaemia, and that it functions via a chromatin based pathway controlling mRNA translation. We have also defined a new RNA modification, internal m7G methylation of miRNAs, mediated by the METTL1 enzyme. We show that this modification affects miRNA processing by disrupting the formation a G-quadrulpex structure. Biologically, m7G methylation by METTL1 regulates cell migration via. The broader function of these and other RNA modifications will be discussed.