Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Nuclear release of eIF1 restricts start-codon selection during mitosis

ABSTRACT: Regulated start-codon selection has the potential to reshape the proteome through the differential production of upstream open reading frames, canonical proteins, and alternative translational isoforms. However, conditions under which start codon selection is altered remain poorly defined. Here, using transcriptome-wide translation-initiation-site profiling, we reveal a global increase in the stringency of start-codon selection during mammalian mitosis. Low-efficiency initiation sites are preferentially repressed in mitosis, resulting in pervasive changes in the translation of thousands of start sites and their corresponding protein products. This enhanced stringency of start-codon selection during mitosis results from increased association between the 40S ribosome and the key regulator of start-codon selection, eIF1. We find that increased eIF1–40S ribosome interaction during mitosis is mediated by the release of a nuclear pool of eIF1 upon nuclear envelope breakdown. Selectively depleting the nuclear pool of eIF1 eliminates the change to translational stringency during mitosis, resulting in altered synthesis of thousands of protein isoforms. In addition, preventing mitotic translational rewiring results in substantially increased cell death and decreased mitotic slippage in cells that experience a mitotic delay induced by anti-mitotic chemotherapies. Thus, cells globally control stringency of translation initiation, which has critical roles during the mammalian cell cycle in preserving mitotic cell physiology.

ORGANISM(S): Homo sapiens

PROVIDER: GSE230189 | GEO | 2023/12/02

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Nuclear release of eIF1 globally increases stringency of start codon selection to preserve mitotic arrest physiology

Project description:Regulated start codon selection has the potential to reshape the proteome through the differential production of uORFs, canonical proteins, and alternative translational isoforms. However, conditions under which start codon selection is altered remain poorly defined. Here, using transcriptome-wide translation initiation site profiling, we reveal a global increase in the stringency of start codon selection during mammalian mitosis. Low-efficiency initiation sites are preferentially repressed in mitosis, resulting in pervasive changes in the translation of thousands of start sites and their corresponding protein products. This increased stringency of start codon selection during mitosis results from increased associations between the 40S ribosome and the key regulator of start codon selection, eIF1. We find that increased eIF1-40S ribosome interactions during mitosis are mediated by the release of a nuclear pool of eIF1 upon nuclear envelope breakdown. Selectively depleting the nuclear pool of eIF1 eliminates the changes to translational stringency during mitosis, resulting in the altered synthesis of thousands of protein isoforms. In addition, preventing mitotic translational rewiring results in substantially increased cell death and decreased mitotic slippage in cells that experience a mitotic delay induced by anti-mitotic chemotherapeutics. Thus, cells globally control translation initiation stringency with critical roles during the mammalian cell cycle to preserve mitotic cell physiology.

2024-10-07 | PXD054183 | Pride

eIF1 modulates the recognition of sub-optimal translation start sites and steers gene expression control mediated by uORFs

Project description:Alternative translation initiation mechanisms such as leaky scanning and reinitiation potentiate the polycistronic nature of transcripts. By allowing for reprogrammed translation, these mechanisms can mediate biological responses to stress stimuli. We combined proteomics with ribosome profiling and mRNA sequencing to identify the biological targets of translation control triggered by eukaryotic translation initiation factor 1 (eIF1), a protein implicated in the stringency of start codon selection. We quantified expression changes of over 4,000 proteins and 10,000 actively translated transcripts, leading to the identification of 245 transcripts undergoing translational control mediated by upstream open reading frames (uORFs) upon eIF1 deprivation. The stringency of start codon selection and preference for optimal nucleotide context were largely diminished leading to translational regulation of uORFs with sub-optimal start sites. Affected genes were implicated in energy production and sensing of metabolic stress. Interestingly, knockdown of eIF1 elicited a synergic response from eIF5 and eIF1B.

2017-01-25 | GSE87328 | GEO

eIF1 modulates the recognition of sub-optimal translation start sites and steers gene expression control mediated by uORFs.

Project description:Alternative translation initiation mechanisms such as leaky scanning and re-initiation potentiate the polycistronic nature of transcripts. By allowing for reprogrammed translation, these mechanisms can mediate biological responses to stress stimuli. We combined proteomics with ribosome profiling and mRNA sequencing to identify the biological targets of translation control triggered by the eukaryotic translation initiation factor 1 (eIF1), a protein implicated in the stringency of start codon selection. We quantified expression changes of over 4,000 proteins and 10,000 actively translated transcripts, leading to the identification of 245 transcripts undergoing translational control mediated by upstream open reading frames (uORFs) upon eIF1 deprivation. The stringency of start codon selection and preference for an optimal nucleotide context were largely diminished leading to translational upregulation of uORFs with sub-optimal start sites. Affected genes were implicated in energy production and sensing of metabolic stress. Interestingly, knockdown of eIF1 elicited a synergic response from eIF5 and eIF1B.

2017-09-13 | PXD004980 | Pride

Evolutionarily Conserved Inhibitory uORFs Sensitize Hox mRNA Translation to Start Codon Selection Stringency

Project description:Translation start site selection in eukaryotes is influenced by context nucleotides flanking the AUG codon and by levels of the eukaryotic translation initiation factors eIF1 and eIF5. In a search of human genes, we identified 5 Hox gene paralogs initiated by AUG codons in conserved suboptimal context as well as 13 Hox genes that contain evolutionarily conserved upstream open reading frames (uORFs) that initiate at AUG codons in poor sequence context. We analyzed published CAGE-seq data and generated CAGE-seq data from mRNAs from mouse somites. These data demonstrate that the 5’ leaders of Hox mRNAs of interest contain conserved uORFs, are much shorter than reported, and lack previously proposed IRES elements. We show that the conserved uORFs inhibit Hox reporter expression and that altering the stringency of start codon selection by overexpressing eIF1 or eIF5 modulates the expression of Hox reporters. We also show that modifying ribosome homeostasis by depleting a large ribosomal subunit protein or treating cells with sublethal concentrations of puromycin leads to lower stringency of start codon selection. Thus, altering global translation can confer gene-specific effects through altered start codon selection stringency.

2022-02-21 | GSE184515 | GEO

eIF1 discriminates against suboptimal initiation sites to prevent excessive uORF translation genome-wide

Project description:The translation pre-initiation complex (PIC) scans the mRNA for an AUG codon in favorable context. Previous findings suggest that the factor eIF1 discriminates against non-AUG start codons by impeding full accommodation of Met-tRNAi in the P site of the 40S ribosomal subunit, necessitating eIF1 dissociation for start codon selection. Consistent with this, yeast eIF1 substitutions that weaken its binding to the PIC increase initiation at UUG codons on a mutant his4 mRNA and particular synthetic mRNA reporters; and also at the AUG start codon of the mRNA for eIF1 itself owing to its poor Kozak context. It was not known however whether such eIF1 mutants increase initiation at suboptimal start codons genome-wide. By ribosome profiling, we show that the eIF1-L96P variant confers increased translation of numerous upstream open reading frames (uORFs) initiating with either near-cognate codons (NCCs) or AUGs in poor context. The increased uORF translation is frequently associated with reduced translation of the downstream main coding sequences (CDS). Initiation is also elevated at the NCCs initiating N-terminal extensions on GRS1 and ALA1 mRNAs, and at a small set of main CDS AUG codons with especially poor context, including that of eIF1 itself. Thus, eIF1 acts throughout the yeast translatome to discriminate against NCC start codons and AUGs in poor context; and impairing this function enhances the repressive effects of uORFs on CDS translation and alters the ratios of protein isoforms translated from near-cognate versus AUG start codons.

2019-10-18 | GSE138599 | GEO

Conformational rearrangements upon start codon recognition in human 48S translation initiation complex

Project description:Selection of the translation start codon is a key step during protein synthesis in human cells. We obtained cryo-EM structures of human 48S initiation complexes and characterized the intermediates of codon recognition by kinetic methods using eIF1A as a reporter. Both approaches capture two distinct ribosome populations formed on an mRNA with a cognate AUG codon in the presence of eIF1A, eIF1, eIF2–GTP–Met-tRNAiMet, eIF3, eIF4A and eIF4B. The ‘open’ 40S subunit conformation differs from the human 48S scanning complex and represents an intermediate preceding the codon recognition step. The ‘closed’ form is similar to reported structures of complexes from yeast and mammals formed upon codon recognition, except for the orientation of eIF1A, which is unique in our structure. Kinetic experiments show how various initiation factors mediate the population distribution of open and closed conformations until 60S subunit docking. Our results provide insights into the timing and structure of human translation initiation intermediates and suggest the differences in the mechanisms of start codon selection between mammals and yeast.

2022-06-09 | PXD031985 | Pride

Nuclear release of eIF1 globally increases translation initiation stringency during mitosis

Project description:Nuclear release of eIF1 globally increases translation initiation stringency during mitosis

| PRJNA957808 | ENA

Study of the eIFG1-eIF1 interaction by TCP-seq on translation initiation in HEK 293T cells

Project description:Start codon recognition by the 48S complex is a critical step in translation. However, understanding the in vivo initiation and its regulation at a global scale is limited. Here, we analyzed translation complex profiling (TCP-seq) data to determine the impact of eIF4G1-eIF1 inhibition and the 48S organization. Our analysis provides the first global view of leaky scanning and reveal the central roles of mRNA features and eIF4G1-eIF1 in its regulation. Specifically, non-leaky genes are enriched with a Kozak bearing a C at -1 position while those with short 5’ UTR with TISU. Additionally, the stability of the 48S complex and its integrity during scanning are impaired upon eIF4G1-eIF1 inhibition. Detailed analysis of initiation site footprints revealed three main classes conserved from yeast to human. Our analysis provides a general overview of AUG selection and evidence for conformational rearrangements in vivo.

2024-03-27 | GSE226132 | GEO

Bi-directional ribosome scanning controls the stringency of start codon selection

Project description:Bi-directional ribosome scanning controls the stringency of start codon selection

| PRJNA734658 | ENA

Selective Translation Complex Profiling in yeast and human Reveals Staged Initiation and Co-translational Assembly of Initiation Factor Complexes [Human]

Project description:Translational control targeting mainly the initiation phase is central to the regulation of gene expression. Understanding all of its aspects requires substantial technological advancements. Here we modified yeast Translational Complex Profile sequencing (TCP-seq), related to ribosome profiling, and adopted it for mammalian cells. Human TCP-seq, capable of capturing footprints of 40S subunits (40Ses) in addition to 80S ribosomes (80Ses), revealed that mammalian and yeast 40Ses distribute similarly across 5’UTRs indicating considerable evolutionary conservation. We further developed a variation called Selective TCP-seq (Sel-TCP-seq) enabling selection for 40Ses and 80Ses associated with an immuno-targeted factor in yeast and human. Sel- TCP-seq demonstrated that eIF2 and eIF3 travel along 5’UTRs with scanning 40Ses to successively dissociate upon start codon recognition. Manifesting the Sel-TCP-seq versatility for gene expression studies, we also identified four initiating 48S conformational intermediates, provided novel insights into ATF4 and GCN4 mRNA translational control, and demonstrated co-translational assembly of initiation factor complexes.

2020-06-26 | GSE139131 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data