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

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

PROVIDER: PRJNA1158720 | ENA |

REPOSITORIES: ENA

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

Project description: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 for in mRNA 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.

2024-12-27 | GSE276695 | GEO

Threonine fuels glioblastoma through YRDC-mediated codon-biased translational reprogramming

Project description:Threonine fuels glioblastoma through YRDC-mediated codon-biased translational reprogramming

| PRJNA955266 | ENA

A snoRNA–tRNA modification network governs codon-biased cellular states

Project description:A snoRNA–tRNA modification network governs codon-biased cellular states

| PRJNA982754 | ENA

A snoRNA–tRNA modification network governs codon-biased cellular states [RMseq]

Project description:A snoRNA–tRNA modification network governs codon-biased cellular states [RMseq]

| PRJNA982109 | ENA

A snoRNA–tRNA modification network governs codon-biased cellular states

Project description:The dynamic balance between tRNA supply and codon usage demand is a fundamental principle in the cellular translation economy. However, the regulation and functional consequences of this balance remain unclear. Here, we use PARIS2 interactome capture, structure modeling, conservation analysis, RNA–protein interaction analysis, and modification mapping to reveal the targets of hundreds of snoRNAs, many of which were previously considered orphans. We identify a snoRNA–tRNA interaction network that is required for global tRNA modifications, including 2′-O-methylation and others. Loss of Fibrillarin, the snoRNA-guided 2′-O-methyltransferase, induces global upregulation of tRNA fragments, a large group of regulatory RNAs. In particular, the snoRNAs D97/D133 guide the 2′-O-methylation of multiple tRNAs, especially for the amino acid methionine (Met), a protein-intrinsic antioxidant. Loss of D97/D133 snoRNAs in human HEK293 cells reduced target tRNA levels and induced codon adaptation of the transcriptome and translatome. Both D97/D133 single and double knockouts in HEK293 cells suppress Met-enriched proliferation-related gene expression programs, including, translation, splicing, and mitochondrial energy metabolism, and promote Met-depleted programs related to development, differentiation, and morphogenesis. In a mouse embryonic stem cell model of development, knockdown and knockout of D97/D133 promote differentiation to mesoderm and endoderm fates, such as cardiomyocytes, without compromising pluripotency, consistent with the enhanced development-related gene expression programs in human cells. This work solves a decade-old mystery about orphan snoRNAs and reveals a function of snoRNAs in controlling the codon-biased dichotomous cellular states of proliferation and development.

2023-09-21 | GSE234689 | GEO

Threonine fuels glioblastoma through YRDC-mediated codon-biased translational reprogramming (Ribosome profiling)

Project description:Threonine fuels glioblastoma through YRDC-mediated codon-biased translational reprogramming (Ribosome profiling)

| PRJNA955270 | ENA

Threonine fuels glioblastoma through YRDC-mediated codon-biased translational reprogramming (RNA-Seq)

Project description:Threonine fuels glioblastoma through YRDC-mediated codon-biased translational reprogramming (RNA-Seq)

| PRJNA955269 | ENA

Threonine fuels glioblastoma through YRDC-mediated codon-biased translational reprogramming (tRNA-Seq)

Project description:Threonine fuels glioblastoma through YRDC-mediated codon-biased translational reprogramming (tRNA-Seq)

| PRJNA1026841 | ENA

A snoRNA–tRNA modification network governs codon-biased cellular states [RNAseq & Riboseq]

Project description:A snoRNA–tRNA modification network governs codon-biased cellular states [RNAseq & Riboseq]

| PRJNA982760 | ENA

A snoRNA–tRNA modification network governs codon-biased cellular states [PARIS2-seq]

Project description:A snoRNA–tRNA modification network governs codon-biased cellular states [PARIS2-seq]

| PRJNA982110 | ENA

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