Chemotherapeutic agents and leucine deprivation induce codon-biased aberrant protein production in cancer.

Autor:	Kochavi A; Division of Oncogenomics, Oncode Institute, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX, Amsterdam, the Netherlands., Nagel R; Division of Oncogenomics, Oncode Institute, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX, Amsterdam, the Netherlands., Körner PR; Division of Oncogenomics, Oncode Institute, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX, Amsterdam, the Netherlands., Bleijerveld OB; NKI Proteomics Facility, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX, Amsterdam, The Netherlands., Lin CP; Division of Molecular Oncology and Immunology, Oncode Institute, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX, Amsterdam, The Netherlands., Huinen Z; Division of Molecular Oncology and Immunology, Oncode Institute, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX, Amsterdam, The Netherlands., Malka Y; Division of Oncogenomics, Oncode Institute, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX, Amsterdam, the Netherlands., Proost N; Preclinical Intervention Unit and Pharmacology Unit of the Mouse Clinic for Cancer and Ageing (MCCA), The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX, Amsterdam, The Netherlands., van de Ven M; Preclinical Intervention Unit and Pharmacology Unit of the Mouse Clinic for Cancer and Ageing (MCCA), The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX, Amsterdam, The Netherlands., Feng X; Division of Oncogenomics, Oncode Institute, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX, Amsterdam, the Netherlands., Navarro JM; Division of Oncogenomics, Oncode Institute, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX, Amsterdam, the Netherlands., Pataskar A; Division of Oncogenomics, Oncode Institute, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX, Amsterdam, the Netherlands., Peeper DS; Division of Molecular Oncology and Immunology, Oncode Institute, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX, Amsterdam, The Netherlands., Champagne J; Division of Oncogenomics, Oncode Institute, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX, Amsterdam, the Netherlands., Agami R; Division of Oncogenomics, Oncode Institute, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX, Amsterdam, the Netherlands.; Erasmus MC, Rotterdam University, Dr. Molewaterplein 40, 3015GD, Rotterdam, the Netherlands.
Jazyk:	angličtina
Zdroj:	Nucleic acids research [Nucleic Acids Res] 2024 Nov 26. Date of Electronic Publication: 2024 Nov 26.
DOI:	10.1093/nar/gkae1110
Abstrakt:	Messenger RNA (mRNA) translation is a tightly controlled process frequently deregulated in cancer. Key to this deregulation are transfer RNAs (tRNAs), whose expression, processing and post-transcriptional modifications are often altered in cancer to support cellular transformation. In conditions of limiting levels of amino acids, this deregulated control of protein synthesis leads to aberrant protein production in the form of ribosomal frameshifting or misincorporation of non-cognate amino acids. Here, we studied leucine, an essential amino acid coded by six different codons. Surprisingly, we found that leucine deprivation leads to ribosomal stalling and aberrant protein production in various cancer cell types, predominantly at one codon, UUA. Similar effects were observed after treatment with chemotherapeutic agents, implying a shared mechanism controlling the downstream effects on mRNA translation. In both conditions, a limitation in the availability of tRNALeu(UAA) for protein production was shown to be the cause for this dominant effect on UUA codons. The induced aberrant proteins can be processed and immune-presented as neoepitopes and can direct T-cell killing. Altogether, we uncovered a novel mode of interplay between DNA damage, regulation of tRNA availability for mRNA translation and aberrant protein production in cancer that could be exploited for anti-cancer therapy. (© The Author(s) 2024. Published by Oxford University Press on behalf of Nucleic Acids Research.)
Databáze:	MEDLINE
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