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

Research output: Contribution to journalArticle (Academic Journal)peer-review

32 Citations (Scopus)

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
Number of pages22
JournalMolecular Cell
Volume81
Issue number22
Early online date24 Sept 2021
DOIs
Publication statusPublished - 18 Nov 2021

Bibliographical note

Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

Keywords

  • Animals
  • Carcinogenesis
  • Cell Membrane/metabolism
  • Disease Progression
  • Drug Resistance, Neoplasm
  • Frameshift Mutation
  • Frameshifting, Ribosomal
  • Humans
  • Immunotherapy/methods
  • MAP Kinase Signaling System
  • Melanoma/metabolism
  • Mice
  • Neoplasms/genetics
  • Oncogenes
  • Peptides/chemistry
  • Protein Biosynthesis
  • Protein Kinase Inhibitors
  • RNA, Messenger/metabolism
  • Ribosomes/metabolism
  • T-Lymphocytes/cytology
  • Tryptophan/chemistry

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