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

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE229673 | GEO | 2024/01/06

REPOSITORIES: GEO

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

Project description:Cancers commonly reprogram translation and metabolism, but little is known about how these two features coordinate in cancer stem cells. Here, we show that glioblastoma stem cells (GSCs) display elevated protein translation. To dissect underlying mechanisms, we performed a CRISPR screen and identified YRDC as the top essential tRNA modification enzymes in GSCs. YRDC catalyses the formation of N6-threonylcarbamoyladenosine (t6A) on ANN-decoding tRNAs (A denotes adenosine and N denotes any nucleotide). Targeting YRDC reduced t6A formation, suppressed global translation, and inhibited tumour growth both in vitro and in vivo. Threonine is an essential substrate of YRDC. Threonine accumulated in GSCs, which facilitated t6A formation through YRDC and shifted the proteome to support mitosis-related genes with ANN codon-bias. Dietary threonine restriction (TR) reduced tumour t6A formation, slowed xenograft growth, and augmented anti-tumour efficacy of chemotherapy and anti-mitotic therapy, providing a molecular basis for a dietary intervention in cancer treatment.

2024-02-22 | PXD049966 | Pride

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

Project description:To understand the underlying mechanism of YRDC, an enzyme catalysing the formation of N6-threonylcarbamoyladenosine (t6A) on ANN-decoding tRNAs, and the interplay between threonine and YRDC in glioblastoma stem cells (GSCs), we carried out comparative transcriptomic analysis in patient-derived GSC456 with or without YRDC deprivation and with or without threonine restriction (control media, 800 μM threonine; threonine-restricted media, 4 μM). To further investigate the translational regulation of YRDC and threonine in GSCs, we performed ribosome profiling in GSC456 with or without YRDC deprivation and with or without threonine restriction (control media, 800 μM threonine; threonine-restricted media, 4 μM). To investigate the effects of YRDC and threonine purtubation on tRNA expression in GSCs, we performed tRNA sequencing in GSC456 with or without YRDC deprivation and with or without threonine restriction (control media, 800 μM threonine; threonine-restricted media, 4 μM).

2024-01-06 | GSE245043 | GEO

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

2024-01-06 | GSE229672 | GEO

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

2024-01-06 | GSE229671 | 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

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

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 (Ribosome profiling)

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

| PRJNA955270 | ENA

Dysfunctional tRNA reprogramming and codon-biased translation in cancer.

Project description:Many cancers hijack translation to increase the synthesis of tumor-driving proteins, the messenger mRNAs of which have specific codon usage patterns. Termed 'codon-biased translation' and originally identified in stress response regulation, this mechanism is supported by diverse studies demonstrating how the 50 RNA modifications of the epitranscriptome, specific tRNAs, and codon-biased mRNAs are used by oncogenic programs to promote proliferation and chemoresistance. The epitranscriptome writers METTL1-WDR4, Elongator complex protein (ELP)1-6, CTU1-2, and ALKBH8-TRM112 illustrate the principal mechanism of codon-biased translation, with gene amplifications, increased RNA modifications, and enhanced tRNA stability promoting cancer proliferation. Furthermore, systems-level analyses of 34 tRNA writers and 493 tRNA genes highlight the theme of tRNA epitranscriptome dysregulation in many cancers and identify candidate tRNA writers, tRNA modifications, and tRNA molecules as drivers of pathological codon-biased translation.

| S-EPMC10071289 | biostudies-literature

tRNA-mediated codon-biased translation in mycobacterial hypoxic persistence.

Project description:Microbial pathogens adapt to the stress of infection by regulating transcription, translation and protein modification. We report that changes in gene expression in hypoxia-induced non-replicating persistence in mycobacteria-which models tuberculous granulomas-are partly determined by a mechanism of tRNA reprogramming and codon-biased translation. Mycobacterium bovis BCG responded to each stage of hypoxia and aerobic resuscitation by uniquely reprogramming 40 modified ribonucleosides in tRNA, which correlate with selective translation of mRNAs from families of codon-biased persistence genes. For example, early hypoxia increases wobble cmo5U in tRNAThr(UGU), which parallels translation of transcripts enriched in its cognate codon, ACG, including the DosR master regulator of hypoxic bacteriostasis. Codon re-engineering of dosR exaggerates hypoxia-induced changes in codon-biased DosR translation, with altered dosR expression revealing unanticipated effects on bacterial survival during hypoxia. These results reveal a coordinated system of tRNA modifications and translation of codon-biased transcripts that enhance expression of stress response proteins in mycobacteria.

| S-EPMC5114619 | biostudies-literature

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