Global and specific mechanisms stimulate mistranslation in cancer

Tryptophan codon-specific mistranslation, in the form of ribosomal frameshifting and tryptophan-to-phenylalanine (W > F) codon reassignments (substitutants), is induced in cancer cells by the limiting level of tryptophan imposed by anti-tumour immunity. While the oncogenic mitogen-activated protein kinase pathway drives frameshifting, whether substitutants are genetically regulated remains unknown. Here we screened for genes that control W > F substitutants following interferon-γ-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 expression of key players in the ribosome quality control pathway, which in turn is essential for mistranslation events. FTSJ1, in contrast, specifically drives W > F mistranslation by methylation of tRNA^Trp to promote its binding to WARS1 loaded with phenylalanine instead of tryptophan. As ADAR1 and FTSJ1 levels are elevated in many cancer types, we propose that cancer cells deploy global and specific mechanisms to promote mistranslation in response to anti-tumour immunity.