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Stem cell function and sensitivity to genotoxic stress is controlled by protein translation rates

ABSTRACT: Whether protein synthesis and cellular stress response pathways interact to control stem cell functions is currently unknown. Here, we show that skin stem cells synthesise less protein than their immediate progenitors in vivo, even when forced to proliferate in a tumour model. Our analyses reveal that activation of stress response pathways drives both a global reduction of protein synthesis and altered translation of specific mRNAs that together promote stem cell functions and tumourigenesis. Mechanistically we show that inhibition of post-transcriptional cytosine-5 methylation locks stem cells in this distinct translational inhibition programme. Paradoxically, this stress-induced translation inhibition renders stem cells hypersensitive to genotoxic stress, as tumour regeneration after treatment with 5-fluorouracil is blocked. Thus, stem cells must revoke translation inhibition pathways to regenerate a tissue or tumour.

ORGANISM(S): Mus musculus

PROVIDER: GSE72067 | GEO | 2016/06/16

SECONDARY ACCESSION(S): PRJNA292860

REPOSITORIES: GEO

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Stem cell function and sensitivity to genotoxic stress is controlled by protein translation rates

Project description:Whether protein synthesis and cellular stress response pathways interact to control stem cell functions is currently unknown. Here, we show that skin stem cells synthesise less protein than their immediate progenitors in vivo, even when forced to proliferate in a tumour model. Our analyses reveal that activation of stress response pathways drives both a global reduction of protein synthesis and altered translation of specific mRNAs that together promote stem cell functions and tumourigenesis. Mechanistically we show that inhibition of post-transcriptional cytosine-5 methylation locks stem cells in this distinct translational inhibition programme. Paradoxically, this stress-induced translation inhibition renders stem cells hypersensitive to genotoxic stress, as tumour regeneration after treatment with 5-fluorouracil is blocked. Thus, stem cells must revoke translation inhibition pathways to regenerate a tissue or tumour. This SuperSeries is composed of the SubSeries listed below.

2016-06-16 | E-GEOD-72067 | biostudies-arrayexpress

Ribosome Profiling of mouse skin squamous tumours

Project description:Purpose: Ribosome profiling has revolutionized systems-based analysis and which produces a âglobal snapshotâ of all the ribosomes translationally active in a cell at a particular moment. The goals of this study are to first apply ribosome profiling to in vivo samples for the first time and in particular to stem cells and tumours and second to determine which mRNAs are being actively translated in these particular situations. Although much is known about gene expression regulation, little is known about how protein translation regulation can affect stem cell differentiation and tumour progression. Methods: several replicates of ribosome and mRNA profiles of wild-type (WT) and NSun2 -/- mouse skin squamous tumours were generated by deep sequencing, using Illumina HiSeq platform. Results: Our analyses reveal that activation of stress response pathways in vivo drives both a global reduction of protein synthesis and altered translation of specific mRNAs that together promote stem cell functions and tumourigenesis. Ribosome profiles of wild-type (WT) and NSun2 -/- mouse skin squamous tumours

2016-06-16 | E-GEOD-72066 | biostudies-arrayexpress

Transfer RNA (tRNA) processing and RNA m5C-methylation profiles of mouse skin squamous tumours

Project description:Purpose: High-throughput RNA sequencing has accelerated discovery of the complex regulatory roles of small RNAs, such those derived from tRNAs. Also recent advances in high-throughput RNA sequencing has revealed the complex RNA modification landscape and the complex role these nucleosides modifactions have in cell signalling, stem cell biology, development and cancer. The goal of this study is to establish how m5C-tRNA methylation and tRNA-derived small RNAs can affect stem cell fucntion in cancer. Methods: four replicates of tRNAs and RNA buisulphite sequencing of wild-type (WT) and NSun2 -/- mouse skin squamous tumours were generated by deep sequencing, using Illumina HiSeq platform. Results: Our analyses reveal that inhibition of post-transcriptional cytosine-5 methylation locks stem cells in this distinct translational inhibition programme that results in tumour progression but that also sentizes cancer cells to genotoxic stress. Transfer RNA (tRNA) sequencing and RNA Bisulphite sequencing of wild-type (WT) and NSun2 -/- mouse skin squamous tumours

2016-06-16 | E-GEOD-72065 | biostudies-arrayexpress

Ribosome Profiling of mouse skin squamous tumours

Project description:Purpose: Ribosome profiling has revolutionized systems-based analysis and which produces a “global snapshot” of all the ribosomes translationally active in a cell at a particular moment. The goals of this study are to first apply ribosome profiling to in vivo samples for the first time and in particular to stem cells and tumours and second to determine which mRNAs are being actively translated in these particular situations. Although much is known about gene expression regulation, little is known about how protein translation regulation can affect stem cell differentiation and tumour progression. Methods: several replicates of ribosome and mRNA profiles of wild-type (WT) and NSun2 -/- mouse skin squamous tumours were generated by deep sequencing, using Illumina HiSeq platform. Results: Our analyses reveal that activation of stress response pathways in vivo drives both a global reduction of protein synthesis and altered translation of specific mRNAs that together promote stem cell functions and tumourigenesis.

2016-06-16 | GSE72066 | GEO

Transfer RNA (tRNA) processing and RNA m5C-methylation profiles of mouse skin squamous tumours

2016-06-16 | GSE72065 | GEO

Inhibition of protein translation under matrix-deprivation stress in breast cancer cells

Project description:Matrix-deprivation stress leads to cell-death by anoikis, whereas overcoming anoikis is critical for cancer metastasis. Work from our lab and others has identified a crucial role for the cellular energy sensor AMPK in anoikis-resistance, highlighting a key role for metabolic reprogramming in stress survival. Protein synthesis is a major energy-consuming process that is tightly regulated under stress. Although an increase in protein synthesis in AMPK-depleted experimentally-transformed MEFs has been associated with anoikis, the status and regulation of protein translation in epithelial-origin cancer cells facing matrix-detachment remains largely unknown. Our study shows that protein translation is mechanistically abrogated at both initiation and elongation stages by the activation of the unfolded protein response (UPR) pathway and inactivation of elongation factor eEF2, respectively. Additionally, we show inhibition of the mTORC1 pathway known for regulation of canonical protein synthesis. We further functionally assay this inhibition using SUnSET assay, which demonstrates repression of global protein synthesis in MDA-MB-231 and MCF7 breast cancer cells when subjected to matrix-deprivation. In order to gauge the translational status of matrix-deprived cancer cells, we undertook polysome profiling. Our data revealed reduced but continuous mRNA translation under matrix-deprivation stress. An integrated analysis of transcriptomic and proteomic data further identifies novel targets that may aid cellular adaptations to matrix-deprivation stress and can be explored for therapeutic intervention.

2023-06-14 | GSE234460 | GEO

Ribosome profiling data obtained from HEK293T cells 30 minutes after treatment with arsenite to a final concentration of 40 M-BM-5M

Project description:Eukaryotic cells rapidly reduce protein synthesis in response to various stress conditions. This can be achieved by the phosphorylation-mediated inactivation of a key translation initiation factor, eIF2. However, the persistent translation of certain mRNAs is required for deployment of an adequate stress response. We carried out ribosome profiling of cultured human cells under conditions of severe stress induced with sodium arsenite. Although this led to a ~4.5-fold general translational repression, the protein coding ORFs of certain individual mRNAs exhibited resistance to the inhibition. Nearly all resistant transcripts possess at least one efficiently translated uORF that repress translation of the main coding ORF under normal conditions. Site specific mutagenesis of two identified stress resistant mRNAs (PPP1R15B and IFRD1) demonstrated that a single uORF is sufficient for eIF2-mediated translation control in both cases. Phylogenetic analysis suggests that at least two regulatory uORFs (namely in SLC35A4 and MIEF1) encode functional protein products. Ribosome profiling of sodium arsenite treated cells for examination of translational response to induction of eIF2 phosphoylation

2015-01-27 | E-GEOD-55195 | biostudies-arrayexpress

Scope and mechanism of eIF4F-independent mRNA translation

Project description:In eukaryotic cells, protein synthesis typically begins with the binding of eIF4F to the 7-methylguanylate (m7G)cap found on the 5’ end of the majority of mRNAs. Surprisingly, overall translational output remains robust under eIF4F inhibition. The sustained protein synthesis has been largely attributed to cap-independent translation mediated by internal ribosome entry sites (IRES). However, the IRES-driven translation is substrate-specific and largely incompatible with the broad spectrum of eIF4F-resistant translatomes.Here, we report that N6-methyladenosine (m6A)-mediated translation prevails on capped mRNAs and is resistant to eIF4F inactivation.Depletion of the methyltransferase METTL3 selectively inhibits translation of mRNAs bearing 5’UTR methylation, but not mRNAs with 5’ terminal oligopyrimidine (TOP) elements. Mechanistically, we identify ABCF1 as a critical mediator of m6A-promoted translation under both stress and physiological conditions. Supporting the role of ABCF1 in m6A-mediated cap-independent translation, ABCF1-sensitive transcripts largely overlap with METTL3-responsible mRNA targets. By illustrating the scope and the mechanism of translation initiation that is neither cap- nor IRES-dependent, these findingsreshape our current perceptions of cellular translational pathways

2017-07-26 | GSE101865 | GEO

Cell-autonomous transcriptional mechanism for enhancement of translation capacity in secretory cells [RNA-Seq IL]

Project description:Translation is a basic cellular process and its capacity is adapted to cell function. In particular, secretory cells achieve high protein synthesis levels without triggering the protein stress response. It is unknown how and when translation capacity is increased during differentiation. Here, we show that the transcription factor Creb3l2 is a scaling factor for translation capacity in pituitary secretory cells and that it directly binds ~75% of regulatory and effector genes for translation. In parallel with this cell-autonomous mechanism, implementation of the physiological UPR pathway prevents triggering the protein stress response. The pituitary differentiation factor Tpit activates Creb3l2 expression, the Creb3l2-dependent regulatory network as well as the physiological UPR pathway. Thus, Creb3l2 implements high basal translation levels through direct targeting of translation effector genes acting downstream of signaling pathways that otherwise regulate protein synthesis. Expression of Creb3l2 may be a useful means to enhance production of therapeutic proteins.

2019-07-29 | GSE132322 | GEO

Cell-autonomous transcriptional mechanism for enhancement of translation capacity in secretory cells [RNA-Seq AtT-20 cells]

2019-07-29 | GSE132321 | GEO

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