Dataset Information

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

ABSTRACT: 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.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Epithelial Cell, Cell Culture

DISEASE(S): Cervix Carcinoma

SUBMITTER: Jimmy Ly

LAB HEAD: Iain Cheeseman

PROVIDER: PXD054183 | Pride | 2024-10-07

REPOSITORIES: Pride

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Dataset's files

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			Action	DRS
	20210524_GS_CellCycle_HeLaWC_TMT.mzML	Mzml
	20210524_GS_CellCycle_HeLaWC_TMT.mzid.gz	Mzid
	20210524_GS_CellCycle_HeLaWC_fx10_CV45_60.raw	Raw
	20210524_GS_CellCycle_HeLaWC_fx10_CV50_65.raw	Raw
	20210524_GS_CellCycle_HeLaWC_fx10_CV55_70.raw	Raw

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

Ly Jimmy J Xiang Kehui K Su Kuan-Chung KC Sissoko Gunter B GB Bartel David P DP Cheeseman Iain M IM

bioRxiv : the preprint server for biology 20240521

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 m ...[more]

PMID: 38617206

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Project description:Mitosis entails global alterations to chromosome structure and nuclear architecture, concomitant with transient silencing of transcription. How cells transmit transcriptional states through mitosis remains incompletely understood. While many nuclear factors dissociate from mitotic chromosomes, the observation that certain nuclear factors and chromatin features remain associated with individual loci during mitosis originated the hypothesis that they could provide transcriptional memory through mitosis. To obtain the first genome-wide view of the dynamics of chromatin structure during mitosis, we compared the DNase sensitivity of interphase and mitotic chromatin at two stages of cellular maturation in a rapidly dividingmurine erythroblastmodel. Despite global chromosome condensation visible during mitosis at the microscopic level, the chromatin accessibility landscape is largely unaltered. However, mitotic chromatin accessibility is locally dynamic, with individual loci maintaining none, some, or all of their interphase accessibility. Mitotic reduction in accessibility occurs primarily within narrow, highly hypersensitive sites that frequently coincide with transcription factor binding sites, whereas broader domains of moderate accessibility tend to be more stable. In mitosis, proximal promoters generally maintain their accessibility, whereas distal regulatory elements preferentially lose accessibility. Promoters with the highest degree of accessibility preservation in mitosis tend to also be accessible across many murine tissues in interphase. Transcription factor GATA1 exerts site-specific changes in interphase accessibility that are most pronounced at distal regulatory elements, but does not visibly influence mitotic accessibility. We conclude that features of open chromatin are remarkably stable through mitosis and are modulated at the level of individual genes and regulatory elements. Dnase-Seq data is integrated with Chip-seq [GSE36589, GSE30142] and RNA-seq to examine epigentic changes in mitosis. We performed DNase-seq on two cell lines, G1E and G1E-ER4, both on an asynchronus population, and on a sample of cells in mitosis; each of the 4 experiments in triplicate.