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Updated: Jun 6, 2025
Identifying Amino Acid Overproducers Using Rare-Codon-Rich Markers
Published on: June 24, 2019
Chemotherapeutic agents and leucine deprivation induce codon-biased aberrant protein production in cancer
Adva Kochavi1, Remco Nagel1, Pierre-Rene Körner1
1Division of Oncogenomics, Oncode Institute, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX, Amsterdam, the Netherlands.
Abstract:
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.
Insights
Cancer cells exploit altered transfer RNA (tRNA) levels to boost protein synthesis. This study reveals that leucine deprivation or chemotherapy causes ribosomal stalling at specific codons, leading to aberrant proteins that can trigger anti-cancer immune responses.
Area of Science:
- Molecular Biology
- Cancer Biology
- Immunology
Background:
- Messenger RNA (mRNA) translation is a critical cellular process often dysregulated in cancer.
- Transfer RNAs (tRNAs) play a key role in cancer-associated translation deregulation, with altered expression, processing, and modifications supporting cellular transformation.
- Under nutrient or stress conditions, aberrant protein synthesis can occur via ribosomal frameshifting or amino acid misincorporation.
Purpose of the Study:
- To investigate the impact of leucine deprivation on mRNA translation and protein production in cancer cells.
- To identify the specific mechanisms and codons affected by leucine limitation.
- To explore the potential therapeutic implications of observed translational alterations in cancer.
Main Methods:
- Utilized various cancer cell types to study the effects of leucine deprivation on protein synthesis.
- Analyzed ribosomal stalling and aberrant protein production, focusing on specific codons like UUA.
- Investigated the role of transfer RNA availability, specifically tRNALeu(UAA), in mediating these effects.
- Examined the consequences of chemotherapeutic agent treatment on mRNA translation.
Main Results:
- Leucine deprivation induced ribosomal stalling and aberrant protein production in cancer cells, predominantly at the UUA codon.
- Similar effects were observed upon treatment with chemotherapeutic agents, suggesting a shared underlying mechanism.
- A limitation in the availability of tRNALeu(UAA) was identified as the cause for the dominant effect on UUA codons.
- Aberrant proteins generated under these conditions can be processed into neoepitopes, potentially directing T-cell mediated killing.
Conclusions:
- Uncovered a novel mechanism linking DNA damage, tRNA availability, and aberrant protein production in cancer.
- Demonstrated that aberrant protein production due to tRNA limitation can elicit anti-cancer immune responses.
- Highlighted a potential new avenue for anti-cancer therapy by exploiting the interplay between translational control and immune activation.
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