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 tRNATrp 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. Wernaart, Fumagalli et al. report ADAR1 and FTSJ1 as regulators of tryptophan-to-phenylalanine substitution in cancer. ADAR1 sustains mistranslation via ribosome quality control. FTSJ1 methylates tRNATrp and allows tRNATrp mischarging by phenylalanine.

Authors

Institutions

Publication Details

Journal
Nature Cell Biology
Published
2026-10-05
DOI
https://doi.org/10.1038/s41556-026-02088-3
Primary Topic
RNA and protein synthesis mechanisms
Type
article
Field-Weighted Citation Impact
0.00
Controls
|||
ALL TIME
JAN
FEB
MAR
APR
MAY
JUN
JUL
AUG
SEP
OCT
article

Global and specific mechanisms stimulate mistranslation in cancer

Demi Wernaart, Pierre-René Körner, Lisanne Giebel, Edwin Sakyi Kyei-Baffour et al.
Nature Cell Biology
RNA and protein synthesis mechanisms
article

Global and specific mechanisms stimulate mistranslation in cancer

Demi Wernaart, Pierre-René Körner, Lisanne Giebel, Edwin Sakyi Kyei-Baffour, Ferhat Alkan, Natalie Proost, Éric Westhof, Marina V. Rodnina, Olaf van Tellingen, Julien Champagne, Artur M Burylo, Onno B. Bleijerveld, Ceri Zwart, Liesbeth Hoekman, Reuven Agami, Alexander Fish, Amos Fumagalli, Mrittika Adhikary, Xiaodong Feng, Cecilia Anna Henriksen, Janne Brouwer, Olaf Geintzer, Chao Yang
article en

Abstract

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 tRNATrp 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. Wernaart, Fumagalli et al. report ADAR1 and FTSJ1 as regulators of tryptophan-to-phenylalanine substitution in cancer. ADAR1 sustains mistranslation via ribosome quality control. FTSJ1 methylates tRNATrp and allows tRNATrp mischarging by phenylalanine.

Nature Cell Biology
Centre National de la Recherche Scientifique (FR), Erasmus MC (NL), The Netherlands Cancer Institute (NL), Max Planck Institute for the Study of Religious and Ethnic Diversity (DE), Oncode Institute (NL), Max Planck Institute of Experimental Medicine (DE), Institut de Biologie Moléculaire et Cellulaire (FR), Wenzhou Institute, University of Chinese Academy of Sciences (CN), Université de Strasbourg (FR), Erasmus University Rotterdam (NL)
Openalex Percentile: Top 21%
RNA and protein synthesis mechanisms
DOIOpen Access PDFOpenAlex
AI Navigator

Ask Laika to Summarize, Analyze, and Connect papers live on the map.

Summarize Papers & Methodologies

Extract key findings, datasets, and comparative methods across publications.

Benchmark Rankings & Visual Analytics

Rank top research institutions, authors, funders, topics, and journals by Field-Weighted Citation Impact (FWCI) and paper volume with instant charts.

Connect Distant Disciplines

Bridge topological clusters on the map to find hidden collaborative intersections.