Abstract

The tricarboxylic acid cycle is a central metabolic pathway used by organisms to generate energy, as well as providing biomolecular building blocks. Mutations in TCA cycle enzymes are a known driver of specific cancer types. One example is loss of function of the fumarate hydratase enzyme in hereditary leiomyomatosis and renal cell cancer. Accumulation of fumarate has previously been shown to inhibit α-ketoglutarate (aKG)-dependent dioxygenases involved in DNA and histone demethylation, however, the link between fumarate accumulation and the epitranscriptome is unclear. We evaluated the effects of fumarate accumulation on different members of the (aKG)-dependent dioxygenases which act upon RNA modifications. We find that fumarate accumulation has a greater effect on the demethylases that act upon N6-methyladenosine (m6A), and that other RNA demethylases are unaffected. Our results suggest that metabolic rewiring in HLRCC impacts different RNA modifications to different extent, leading to changes in gene expression that might support disease progression.