Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Anaphase-promoting complex-dependent control of cell identity

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE122298 | GEO | 2020/02/03

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

SUMO targets the APC/C in a phosphorylation-dependent manner to regulate transition from metaphase to anaphase

Project description:Signal transduction by Small Ubiquitin-like Modifier (SUMO) regulates a myriad of nuclear processes. Here, we report on the role of SUMO in mitosis in human cell lines. Knocking down the SUMO conjugation machinery resulted in a delay in mitosis and defects in mitotic chromosome separation. Searching for relevant SUMOylated proteins in mitosis, we identified the APC/C complex, a master regulator of metaphase to anaphase transition, as a SUMO target. The APC4 subunit is the major SUMO target in the complex, containing SUMO acceptor lysines at positions 772 and 798. SUMOylation increased APC/C ubiquitylation activity towards a subset of its targets, including the newly identified target KIF18B. Intriguingly, SUMOylation of APC/C was regulated by casein kinase driven phosphorylation of serines at positions 777 and 779. Combined, our findings demonstrate the importance of SUMO signal transduction for genome integrity during mitotic progression and reveal a triad of PTMs, cooperating to drive mitosis.

2018-09-19 | PXD006335 | Pride

The E3 ubiquitin ligase HECTD1 contributes to cell proliferation through an effect on mitosis

Project description:Mechanistic studies of how protein ubiquitylation regulates the cell cycle, in particular during mitosis, have provided unique insights which have contributed to the emergence of the ‘Ubiquitin code’. In contrast to RING E3 ubiquitin ligases such as the APC/c ligase complex, the contribution of other E3 ligase families during cell cycle progression remains less well understood. Similarly, the roles of ubiquitin chain types beyond homotypic K48 chains in S-phase or branched K11/K48 chains during mitosis, also remains to be fully determined. Our recent findings that HECTD1 ubiquitin ligase activity assembles branched K29/K48 ubiquitin linkages prompted us to evaluate its function during the cell cycle. We used transient knockdown and genetic knockout to show that HECTD1 depletion in HEK293T and HeLa cells decreases cell number and we established that this is mediated through loss of ubiquitin ligase activity. Interestingly, we found that HECTD1 depletion increases the proportion of cells with aligned chromosomes (Prometa/Metaphase) and we confirmed this molecularly using phospho-Histone H3 (Ser28) as a marker of mitosis. Time-lapse microscopy of NEBD to anaphase onset established that HECTD1-depleted cells take on average longer to go through mitosis. To explore the underlying mechanisms, we used proteomics and identified the interactome of endogenous HECTD1 in cells synchronized in mitosis and validated the Mitosis Checkpoint Complex protein BUB3 as a novel HECTD1 interactor. In line with this, we found that HECTD1 depletion reduces the activity of the Spindle Assembly Checkpoint. Overall, our data suggests a novel role for HECTD1 ubiquitin ligase activity during mitosis.

2022-08-03 | PXD035503 | Pride

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.

2022-03-11 | GSE181639 | GEO

The ubiquitin E3 ligase APC/CCdc20 mediates mitotic degradation of OGT

Project description:O-linked β-N-acetylglucosamine (O-GlcNAc) transferase (OGT) is the sole enzyme that catalyzes all O-GlcNAcylation reactions intracellularly. Previous investigations have found that OGT levels oscillate during the cell division process. Specifically, OGT abundance is downregulated during mitosis, but the underlying mechanism is lacking. Here we demonstrate that OGT is ubiquitinated by the ubiquitin E3 ligase, anaphase promoting complex/cyclosome (APC/C)-cell division cycle 20 (Cdc20). We show that APC/CCdc20 interacts with OGT through a conserved destruction box (D-box): Arg-351/Leu-354, the abrogation of which stabilizes OGT. As APC/CCdc20-substrate binding is often preceded by a priming ubiquitination event, we also used mass spectrometry and mapped OGT Lys-352 to be a ubiquitination site, which is a prerequisite for OGT association with APC/C subunits. Interestingly in The Cancer Genome Atlas, R351C is a uterine carcinoma mutant, suggesting that mutations of the D-box are linked with tumorigenesis. Paradoxically, we found that both R351C and the D-box mutants (R351A/L354A) inhibit uterine carcinoma in mouse xenograft models, probably due to impaired cell division and proliferation. In sum, we propose a model where OGT Lys-352 ubiquitination primes its binding with APC/C, and then APC/CCdc20 partners with OGT through the D-box for its mitotic destruction. Our work not only highlights the key mechanism that regulates OGT during the cell cycle, but also reveals the mutual coordination between glycosylation and the cell division machinery.

2024-08-10 | PXD050552 | Pride

Lactate regulates cell cycle and proliferation by remodeling the anaphase promoting complex

Project description:Lactate is abundant in rapidly dividing cells, due to the requirement for elevated glucose catabolism to support proliferation. However, it is not known whether accumulated lactate affects the proliferative state. Here, we deploy a systematic approach to determine lactate-dependent regulation of proteins across the human proteome. From this data, we elucidate a mechanism of cell cycle regulation whereby accumulated lactate activates the anaphase promoting complex (APC/C). Remodeling of APC/C in this way is caused by direct inhibition of the SUMO protease SENP1 by lactate. We discover that accumulated lactate binds and inhibits SENP1 by forming a complex with zinc in the SENP1 active site. SENP1 inhibition by lactate stabilizes SUMOylation of two residues on APC4, which are required to reorient APC/C to allow UBE2C binding and thus increase APC/C activity. This direct regulation of APC/C by lactate is required to stimulate timed degradation of cell cycle proteins, and efficient mitotic exit in proliferative mammalian cells. The above mechanism is initiated upon mitotic entry when lactate abundance reaches its apex. In this way, accumulation of lactate communicates the consequences of a nutrient replete growth phase to stimulate timed opening of APC/C, cell division, and proliferation. Conversely, we show that aberrant remodeling of APC/C by lactate occurs when lactate concentrations are chronically elevated, which is a hallmark of numerous cancers. Moreover, persistent lactate accumulation overcomes anti-mitotic pharmacology to drive mitotic slippage via the newfound mode of APC/C activation. Taken together, we define a biochemical mechanism through which lactate directly regulates protein function to control cell cycle and proliferation.

2023-02-07 | PXD036641 | Pride

CDK9-55 guides the anaphase-promoting complex/cyclosome (APC/C) in choosing the DNA repair pathway by affecting the UFL1 ubiquitination.

Project description:DNA double-strand breaks (DSBs) contribute to genome instability, a key feature of cancer. DSBs are mainly repaired by homologous recombination (HR) and non-homologous end-joining (NHEJ). We investigated the role of an isoform of the multifunctional cyclin-dependent kinase 9, CDK9-55, in DNA repair, by generating CDK9-55-knockout HeLa clones (through CRISPR-36 Cas9), which showed potential HR dysfunction. A phosphoproteomic screening in these clones treated with camptothecin revealed that CDC23 (cell division cycle 23), a component of the E3 ubiquitin ligase APC/C (anaphase-promoting complex/cyclosome), is a new substrate of CDK9-55, with S588 being its putative phosphorylation site. Mutated non-phosphorylatable CDC23(S588A) affected the repair pathway choice by impairing HR and favouring error prone NHEJ. Moreover, CDC23(S588A) promoted the ubiquitination of UFL1, a recently identified HR player. Overall, CDK9-55 could guide APC/C in choosing the correct DNA repair pathway, possibly by regulating UFL1 stability. This CDK9 role should be considered when designing CDK-inhibitor-based cancer therapies.

2021-07-20 | MSV000087856 | MassIVE

Quantitative proteomics in G1 cells reveals the insulin receptor adaptor IRS2 as an APC/CCdh1 substrate

Project description:The anaphase promoting complex/cyclosome (APC/C) is a ubiquitin ligase that controls progression through the eukaryotic cell cycle by targeting key substrates for degradation through the ubiquitin proteasome pathway. During G1, the APC/C works in concert with its co-activator Cdh1 to recognize and ubiquitinate specific substrates during this phase of the cell cycle. While many APC/CCdh1 substrates play a role cell cycle regulation, others are involved in distinct cellular processes, indicating that diverse biological pathways are subject to APC/C-mediated control. To identify novel pathways and substrates regulated by APC/CCdh1, we conducted an unbiased proteomic screen in G1-arrested RPE1 cells acutely treated with small molecule APC/C inhibitors. Combining these results with degron prediction analysis, we discovered a range of putative APC/C substrates. We validated IRS2, a key adaptor protein involved in signaling downstream of the insulin and IGF1 receptors, as a novel direct APC/CCdh1 target. We demonstrate that genetic deletion of IRS2 reduces the expression of proteins involved in cell division and functionally impairs the spindle assembly checkpoint. Together, these findings reveal a novel connection between the insulin/IGF1 signaling network and the cell cycle regulatory machinery.

2020-06-22 | PXD018329 | Pride

A degradation motif in STAU1 defines a novel family of proteins involved in inflammation

Project description:Cancer development is regulated by inflammation. Staufen 1 (STAU1) is an RNA-binding protein whose expression level is critical in cancer cells as it is related to cell proliferation or cell death. STAU1 expression levels are downregulated during mitosis due to its degradation by the E3 ubiquitin ligase anaphase-promoting complex/cyclosome (APC/C). In this paper, we map the molecular determinant involved in STAU1 degradation in mitosis to amino acids 38-50 and, by alanine scanning, we shorten the motif to F39PxPxxLxxxxL50 (FPL-motif). Mutation of the FPL-motif prevents STAU1 degradation by APC/C. Interestingly, a search in databases reveals that the FPL-motif is shared by 15 additional proteins most of them being involved in inflammation. We show that one of these proteins, MAP4K1, is indeed degraded via the FPL-motif; however, it is not a target of APC/C. Using proximity labeling with STAU1, we identify TRIM25, an E3-ubiquitin ligase involved in the innate immune response and interferon production, as responsible for STAU1 and MAP4K1 degradation, dependent on the FPL-motif. These results are consistent with previous studies that linked STAU1 to cancer-induced inflammation and identify a novel degradation motif that likely coordinates a novel family of proteins involved in inflammation.

2023-02-21 | PXD037703 | Pride

A degradation motif in STAU1 defines a novel family of proteins involved in inflammation

2023-03-11 | PXD036675 | Pride

Multiple modes of regulation control dynamic transcription patterns during the mitosis-G1 transition

Project description:Following cell division, genomes must reactivate gene expression patterns that reflect the identity of the cell. Here, we use PRO-seq to examine the mechanisms that reestablish transcription patterns after mitosis. We uncover regulation of the transcription cycle at multiple steps including initiation, promoter-proximal pause positioning and escape, poly-A site cleavage and termination during the mitotic-G1 transition. During mitosis, RNA polymerase activity is retained at initiation sites, albeit shifted in position relative to non-mitotic cells. This activity is strongly linked to maintenance of local chromatin architecture during mitosis and is more predictive of rapid gene reactivation than histone modifications previously associated with bookmarking. These molecular bookmarks, combined with sequence-specific transcription factors, direct expression of select cell growth and cell specific genes during mitosis followed by reactivation of functional gene groups with distinct kinetics after mitosis. This study details how dynamic regulation of transcription at multiple steps contributes to gene expression during the cell cycle.

2022-04-15 | GSE179576 | 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