Specific chemical modifications of biological molecules are an efficient way of regulating molecular function, and a plethora of downstream signalling pathways are influenced by the modification of DNA and proteins.

Many of the enzymes responsible for regulating protein and DNA modifications are targets of current cancer therapies. RNA epitranscriptomic, the study of RNA modifications, is the new frontier in this arena. Increasing evidence suggests that RNA modification pathways are also mis regulated in human cancers and may be ideal targets for cancer therapy.

Trimethyl Guanosine Synthase (TGS1) mediates the dimethylation of RNA 5’-cap 7-methylguanosine to generate 2,2,7-trimethylguanosine. We found that TGS1 can directly methylate a large number of mRNAs encoding mitochondrial proteins, promoting their translation. Among them, we identified critical components of complexes involved in the TCA cycle.

TGS1 depletion affects mitochondrial metabolism and, in turn, impairs the growth of acute myeloid leukaemia cells. Additionally, we demonstrate that TGS1 depletion can sensitize leukaemia cells to small-molecule inhibitors inducing ferroptosis or inhibiting mitochondrial function.