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Regulation of protein translation during mitosis

ABSTRACT: Entry into and exit from mitosis is driven by precisely-timed changes in protein abundance, and involves transcriptional regulation and protein degradation. However, the role of translational regulation in modulating cellular protein content during mitosis remains poorly understood. Here, using ribosome profiling, we show that translational, rather than transcriptional regulation is the dominant mechanism for modulating protein synthesis at mitotic entry. The vast majority of regulated mRNAs are translationally repressed, which contrasts previous findings of selective mRNA translational activation at mitotic entry. One of the most pronounced translationally repressed genes in mitosis is Emi1, an inhibitor of the anaphase promoting complex (APC), which is degraded during mitosis. We show that Emi1 degradation is insufficient for full APC activation and that simultaneous translational repression is required. These results provide a genome-wide view of protein translation during mitosis and suggest that translational repression may be used to ensure complete protein inactivation

ORGANISM(S): Homo sapiens

PROVIDER: GSE67902 | GEO | 2015/09/01

SECONDARY ACCESSION(S): PRJNA281177

REPOSITORIES: GEO

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Regulation of protein translation during mitosis

Project description:Entry into and exit from mitosis is driven by precisely-timed changes in protein abundance, and involves transcriptional regulation and protein degradation. However, the role of translational regulation in modulating cellular protein content during mitosis remains poorly understood. Here, using ribosome profiling, we show that translational, rather than transcriptional regulation is the dominant mechanism for modulating protein synthesis at mitotic entry. The vast majority of regulated mRNAs are translationally repressed, which contrasts previous findings of selective mRNA translational activation at mitotic entry. One of the most pronounced translationally repressed genes in mitosis is Emi1, an inhibitor of the anaphase promoting complex (APC), which is degraded during mitosis. We show that Emi1 degradation is insufficient for full APC activation and that simultaneous translational repression is required. These results provide a genome-wide view of protein translation during mitosis and suggest that translational repression may be used to ensure complete protein inactivation Ribosome profiling and mRNA-seq from 3 time points in the cell cycle

2015-09-01 | E-GEOD-67902 | biostudies-arrayexpress

Proteomic analysis of the physiological E3 ubiquitin ligase responsible for PIN1 degradation

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Transcription profiling analysis of human global and individual mRNA translational efficiencies

2005-10-31 | E-SMDB-2546 | biostudies-arrayexpress

Regulated interaction of ID2 with the anaphase-promoting complex links progression through mitosis with reactivation of cell-type-specific transcription

Project description:Tissue-specific transcriptional activity is silenced in mitotic cells but it remains unclear whether the mitotic regulatory machinery interacts with tissue-specific transcriptional programs. We show that such cross-talk involves the controlled interaction between core subunits of the anaphase-promoting complex (APC) and the ID2 substrate. The N-terminal region of ID2 bound to core APC subunits, which formed an ID2-compatible pocket that optimally oriented ID2 in the APC-CDH1 complex. Phosphorylation of serine-5 by CDK1 prevented the association of ID2 with core APC, impaired ubiquitylation and stabilized ID2 protein at the mitosis-G1 transition leading to inhibition of basic Helix-Loop-Helix (bHLH)-mediated transcription. The serine-5 phosphomimetic mutant of ID2 that inefficiently bound core APC remained stable during mitosis, delayed exit from mitosis and reloading of bHLH transcription factors on chromatin. It also locked cells into a “mitotic stem cell” transcriptional state resembling the pluripotent program of embryonic stem cells. The substrates of APC-CDH1 SKP2 and Cyclin B1 share with ID2 the phosphorylation-dependent, D-box-independent interaction with core APC. These results reveal a new layer of control of the mechanism by which substrates are recognized by APC.

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APC/CCdc20 dependent degradation of Clb4 is all there is to astral microtubule stabilization

Project description:Coordination between sister chromatid separation and segregation is crucial for accurate chromosome partitioning to the offspring. Key to this process is the ability of mitotic spindle microtubules to respond to different molecular signals and remodel their dynamics accordingly. Based on their function, spindle microtubules are conventionally divided into three classes: kinetochore, interpolar and astral microtubules (kMTs, iMTs and aMTs, respectively). While different mechanisms have been proposed to control kMT and iMT dynamics, aMT regulation remains elusive. We here show that aMT dynamics are tightly regulated. aMTs remain unstable up to metaphase to control spindle orientation and are stabilized at anaphase onset. Necessary and sufficient for this stabilization is the degradation of the mitotic cyclin Clb4 mediated by the Anaphase Promoting Complex in combination with its activator subunit Cdc20 (APC/CCdc20). Our results contribute to delineate a comprehensive picture of late mitotic events, where individual steps of the signalling cascade initiated by APC/CCdc20 activation and culminating in cohesin cleavage time the final stages of mitosis by sequentially modulating the dynamics of the three classes of spindle microtubules.

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IRES containing mRNAs and mitotic cell cycle

Project description:A cell synchronization protocol was established in which global and individual mRNA translational efficiencies could be examined. While global translational efficiency was reduced in mitotic cells, approximately 3% of mRNAs remained predominantly associated with large polysomes during mitosis, as determined by cDNA microarray analyses. The 5 noncoding regions of six mRNAs were shown to contain internal ribosome entry sites (IRES). However, not all known mRNAs that contain IRES elements were actively translated during mitosis, arguing that specific IRES sequences are differentially regulated during mitosis. A cell cycle design experiment design type is one that assays events that occurs in relation to the cell cycle, which is the period between the formation of a cell, by division of its mother cell and the time when the cell itself divides to form two daughter cells. User Defined

2005-12-30 | E-GEOD-3957 | biostudies-arrayexpress

Nuclear release of eIF1 globally increases translation initiation stringency during mitosis

Project description:Regulated translation initiation has the potential to reshape the proteome, but conditions under which start codon selection is altered remain poorly defined. Here, using global translation initiation site profiling, we reveal widespread changes in start codon selection during the mammalian cell cycle. Low-efficiency initiation sites are preferentially repressed in mitosis, resulting in changes in the relative translation of thousands of annotated proteins, alternative translational isoforms, and uORFs. This increased mitotic translational stringency results from the cytoplasmic release of a nuclear pool of eIF1 upon nuclear envelope breakdown. Increased eIF1-40S ribosome interactions repress suboptimal initiation sites to rewire the mitotic proteome. Selectively depleting the nuclear pool of eIF1 eliminates changes to translational stringency during mitosis, resulting in substantially increased cell death following an extended mitotic delay induced by anti-mitotic chemotherapeutics. Thus, cells globally control translation initiation stringency to alter their physiology with critical roles during the mammalian cell cycle.

2023-12-02 | GSE230189 | GEO

Anaphase-promoting complex-dependent control of cell identity

Project description:Tissue development and homeostasis rely on the proliferation of progenitor cells, whose identities are established by tightly controlled gene expression networks. However, mRNA synthesis is inhibited during mitosis, and the transcriptional programs that define a cell type must be restarted upon entry into each new cell cycle; how this is accomplished is poorly understood. Here, we identified a ubiquitin-dependent mechanism that integrates gene expression with cell division to preserve cell identity. We found that WDR5 and TBP, which bind active promoters during interphase, recruit the E3 ligase anaphase-promoting complex (APC/C) to specific transcription start sites during mitosis. This allows the APC/C to locally decorate histones with K11/K48-linked ubiquitin chains, which destabilizes nucleosomes and ensures continued gene expression in the next cell cycle. Mitotic exit and transcription re-initiation are therefore controlled by the same essential regulator, the APC/C, which provides a robust mechanism to maintain cell identity through cell division.

2020-02-03 | GSE122298 | GEO

Mitotic post-translational modifications of histones promote chromatin compaction in vitro

Project description:As histones undergo major changes in their post-translational modifications during mitotic entry, we speculated that the spectrum of cell cycle-specific histone modifications might contribute to chromosome compaction during mitosis. To test this hypothesis, we isolated core histones from interphase and mitotic cells and reconstituted chromatin with them. We used mass spectrometry to show that key post-translational modifications remained intact during our isolation procedure.

2018-10-24 | PXD007116 | Pride

Kinases orchestrate phospho-proteome dynamics during mitotic exit

Project description:The cell division cycle culminates in mitosis when two daughter cells are born. As cyclin-dependent kinase (Cdk) activity reaches its peak, the Anaphase Promoting Complex (APC) is activated to trigger sister chromatid separation and mitotic spindle elongation, followed by spindle disassembly and cytokinesis. Degradation of mitotic cyclins and activation of Cdk-counteracting phosphatases are thought to cause protein dephosphorylation to control these sequential events. Here, we use budding yeast to analyze phosphorylation dynamics of 3456 phosphosites on 1101 proteins with high temporal resolution as cells progress synchronously through mitosis. This illustrates sequential protein dephosphorylation and reveals that the order arises from successive inactivation of S and M phase Cdks and of the mitotic kinase Polo. Unexpectedly, we detect as many new phosphorylation events as there are dephosphorylation events. These correlate with late mitotic kinase activation and identify numerous candidate targets of these kinases. Our findings revise our view of mitotic exit and portray it as a dynamic process in which a range of mitotic kinases instruct the order of both protein dephosphorylation as well as phosphorylation.

2018-10-15 | PXD008327 | Pride

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