Global and specific mechanisms stimulate mistranslation in cancer

While frameshifting is driven by the oncogenic MAPK pathway, whether substitutants are genetically regulated is unknown. Here, we screened for genetic mechanisms that control W>F substitutants following IFNγ-mediated tryptophan shortage.

This screen identified ADAR1, an enzyme that converts adenosine to inosine in double-stranded RNA molecules, and FTSJ1, an enzyme that 2’-O-methylates the anticodon region of several tRNAs. We demonstrate that ADAR1 sustains the expression of key players of the ribosome quality control pathway, which in turn is essential for mistranslation events. FTSJ1, in contrast, specifically drives W>F mistranslation by methylation of tRNATrp to promote its binding to WARS1 loaded with phenylalanine instead of tryptophan.