Oncogene-dependent sloppiness in mRNA translation

Julien Champagne, Abhijeet Pataskar, Naomi Blommaert, Remco Nagel, Demi Wernaart, Sofia Ramalho, Juliana Kenski, Onno B. Bleijerveld, Esther A. Zaal, Celia R. Berkers, Maarten Altelaar, Daniel S. Peeper, William J. Faller, Reuven Agami*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

31 Citations (Scopus)
14 Downloads (Pure)

Abstract

mRNA translation is a highly conserved and tightly controlled mechanism for protein synthesis. Despite protein quality control mechanisms, amino acid shortage in melanoma induces aberrant proteins by ribosomal frameshifting. The extent and the underlying mechanisms related to this phenomenon are yet unknown. Here, we show that tryptophan depletion-induced ribosomal frameshifting is a widespread phenomenon in cancer. We termed this event sloppiness and strikingly observed its association with MAPK pathway hyperactivation. Sloppiness is stimulated by RAS activation in primary cells, suppressed by pharmacological inhibition of the oncogenic MAPK pathway in sloppy cells, and restored in cells with acquired resistance to MAPK pathway inhibition. Interestingly, sloppiness causes aberrant peptide presentation at the cell surface, allowing recognition and specific killing of drug-resistant cancer cells by T lymphocytes. Thus, while oncogenes empower cancer progression and aggressiveness, they also expose a vulnerability by provoking the production of aberrant peptides through sloppiness.

Original languageEnglish
Pages (from-to)4709-4721.e9
JournalMolecular Cell
Volume81
Issue number22
DOIs
Publication statusPublished - 23 Nov 2021

Bibliographical note

Funding Information:
R.A. is supported by the Dutch Cancer Society (KWF projects 13647, 11574 ), the European Research Council ( ERC-PoC #665317 and ERC-AdG #832844 ), and the Dutch Science Organization ( NWO-TOP #91216002 ). A.P. is supported by a long-term EMBO fellowship grant ( EMBO ALTF 796-2018 ). O.B.B. and M.A. are supported by the Dutch NWO X-omics Initiative . We are grateful to George Georgiou and Everett Stone for the kynureninase gift. We would like to express our thanks to all of the members of the Agami lab for very fruitful discussions.

Publisher Copyright:
© 2021 The Authors

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