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 language | English |
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Pages (from-to) | 4709-4721.e9 |
Journal | Molecular Cell |
Volume | 81 |
Issue number | 22 |
DOIs | |
Publication status | Published - 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