Ontology highlight
ABSTRACT:
PROVIDER: PRJNA877059 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR21429573_1.fastq.gz | Fastqsanger.gz | |||
| SRR21429573_2.fastq.gz | Fastqsanger.gz | |||
| SRR21429574_1.fastq.gz | Fastqsanger.gz | |||
| SRR21429574_2.fastq.gz | Fastqsanger.gz | |||
| SRR21429575_1.fastq.gz | Fastqsanger.gz |
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Project description:The role of Rad53 in response to a DNA lesion is central for the accurate orchestration of the DNA damage response. Rad53 activation relies on its phosphorylation by the Mec1 kinase and its own autophosphorylation in a manner dependent on the adaptor Rad9. While the mechanism behind Rad53 phosphorylation and activation has been well documented, less is known about the processes that counteract its kinase activity during the response to a DNA break. Here, we describe that PP4 dephosphorylates Rad53 during the repair of a DNA lesion, a process that affects the phosphorylation status of multiple factors involved in the DNA damage response. PP4-dependent Rad53 dephosphorylation stimulates DNA end resection in a process that relies mainly on Sgs1/Dna2. Consequently, elimination of PP4 activity affects DNA resection and repair by single-strand annealing, defects that are bypassed by reducing the hyper-phosphorylation state of Rad53 observed in the absence of the phosphatase. These results confirms that Rad53 is one of the principal targets of PP4 during the repair of a DNA lesion and demonstrate that the attenuation of its kinase activity during the initial steps of the repair process is essential to efficiently enhance recombinational repair pathways that depend on long-range resection for its execution.
2019-09-12 | PXD013782 | Pride
Project description:DNA double-strand breaks (DSBs) can be repaired by several pathways. In eukaryotes, repair pathway choice – the cellular decision making underlying DSB repair – occurs at the level of DSB resection and is controlled by the cell cycle. Upon cell cycle-dependent activation, cyclin-dependent kinases (CDKs) phosphorylate resection proteins and thereby stimulate DSB resection and repair by homologous recombination (HR). Here, we identify Dbf4-dependent kinase (DDK) as a second major cell cycle regulator of DNA end resection. Using inducible genetic and chemical inhibition of DDK in budding yeast and human cells, we show that DNA resection and HR require activation by DDK. Mechanistically, DDK catalyzes phosphorylation of at least two resection nucleases. Via phosphorylation of the Mre11 activator Sae2 it promotes activation of resection initiation, via phosphorylation of the Dna2 nuclease it promotes long-range resection. Notably, synthetic activiation of DDK allows limited resection and HR in G1 cells, suggesting that DDK is a key component of DSB repair decision making.
2024-02-22 | GSE233549 | GEO
Project description:Schizosaccharomyces pombe Clp1 is a Cdc14-family phosphatase that reverses mitotic Cdk1 phosphorylation. Despite evolutionary conservation, Clp1’s mammalian orthologs do not share this function. Rather, higher eukaryotic Cdc14 enzymes act in DNA repair, ciliogenesis, and gene regulation. To examine if Clp1 regulates gene expression, we compared the transcriptional profiles of cells lacking Clp1 function to that of wildtype. Because clp1∆ cells are sensitive to the actin depolymerizing drug, LatrunculinA, we also investigated whether a transcriptional response was involved. Our results indicate that Clp1 does not detectably affect gene expression and highlight the organism-specific functions of this conserved phosphatase family.
2024-03-11 | GSE255124 | GEO
Project description:This model is from the article:
Downregulation of PP2A(Cdc55) phosphatase by separase initiates mitotic exit in budding yeast.
Queralt E, Lehane C, Novak B, Uhlmann F. Cell.
2006 May 19;125(4):719-32. 16713564
,
Abstract:
After anaphase, the high mitotic cyclin-dependent kinase (Cdk) activity is downregulated to promote exit from mitosis. To this end, in the budding yeast S. cerevisiae, the Cdk counteracting phosphatase Cdc14 is activated. In metaphase, Cdc14 is kept inactive in the nucleolus by its inhibitor Net1. During anaphase, Cdk- and Polo-dependent phosphorylation of Net1 is thought to release active Cdc14. How Net1 is phosphorylated specifically in anaphase, when mitotic kinase activity starts to decline, has remained unexplained. Here, we show that PP2A(Cdc55) phosphatase keeps Net1 underphosphorylated in metaphase. The sister chromatid-separating protease separase, activated at anaphase onset, interacts with and downregulates PP2A(Cdc55), thereby facilitating Cdk-dependent Net1 phosphorylation. PP2A(Cdc55) downregulation also promotes phosphorylation of Bfa1, contributing to activation of the "mitotic exit network" that sustains Cdc14 as Cdk activity declines. These findings allow us to present a new quantitative model for mitotic exit in budding yeast.
This model originates from BioModels Database: A Database of Annotated Published Models (http://www.ebi.ac.uk/biomodels/). It is copyright (c) 2005-2012 The BioModels.net Team.
For more information see the terms of use
.
To cite BioModels Database, please use: Li C, Donizelli M, Rodriguez N, Dharuri H, Endler L, Chelliah V, Li L, He E, Henry A, Stefan MI, Snoep JL, Hucka M, Le Novère N, Laibe C (2010) BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. BMC Syst Biol., 4:92.
2024-09-02 | BIOMD0000000409 | BioModels
Project description:In the quantitative model for cell cycle control, progression from G1 through S phase and into mitosis is ordered by thresholds of increasing cyclin-dependent kinase (Cdk) activity. How such thresholds are read out by substrates, that respond with the correct phosphorylation timing, if not known. In budding yeast, Cdk phosphorylates its many substrates with widely varying efficiencies, but there is no obvious correlation between phosphorylation efficiency and timing. Instead, we explore here whether Cdk-counteracting phosphatases impose Cdk thresholds. We find that the abundant PP2ACdc55 phosphatase counteracts Cdk phosphorylation in interphase and delays phosphorylation of late Cdk substrates, an effect that is independent of its known impact on the Cdk tyrosine phosphorylation status. Strikingly, PP2ACdc55 specifically counteracts phosphorylation of threonine residues. Consequently, we find that threonine-directed phosphorylation occurs late in the cell cycle, compared to serine phosphorylation. Late phosphorylation of Ndd1, a model substrate, depends on threonine identity. Our results support a model in which phosphatases contribute to ordering cell cycle progression by directly counteracting Cdk phosphorylation and unveil a principle of cell cycle control based on the phosphoacceptor amino acid.
2017-01-23 | PXD004461 | Pride
Project description:We have previously shown that the Cdc14 phosphatase is essential for an efficient repair of a DNA lesion, however we still missing how the phosphatase exerts this molecular functions and what are its targets during the repair process. To identify Cdc14 phospho-targets in response to DNA damage, we performed mass spectrometry analysis of Wild-type and Cdc14 deficient cells before and after inducing a single DSBs by expressing the HO endonuclease. Wild-type and a thermosensitive allele cdc14-1 were grown overnight and blocked in G2/M by using nocodazole to avoid cell cycle-dependent changes in protein phosphorylation between both strains. After the block was attained, cells were transfer to 37C to deplete Cdc14 activity prior HO induction. By, using this approach we have screened for proteins containing quantitate low levels of phosphorylated residues after the induction of the DNA lesion that occurs only when Cdc14 is active.
2016-12-22 | PXD004966 | Pride
Project description:CDC14 phosphatases are critical components of the cell cycle machinery that drives exit from mitosis in yeast. However, the two mammalian paralogs, CDC14A and CDC14B, are dispensable for cell cycle progression or exit, and their function remains unclear. By generating a double Cdc14a; Cdc14b -null mouse model, we report here that CDC14 phosphatases control cell differentiation in pluripotent cells, and their absence results in deficient development of the neural system. Lack of CDC14 impairs neural differentiation from embryonic stem cells (ESCs) accompanied by deficient induction of genes controlled by bivalent promoters. CDC14 directly dephosphorylates and destabilizes Undifferentiated embryonic Transcription Factor 1 (UTF1) during the exit from stemness. Multiomic single-cell analysis of differentiating ESCs suggest that increased UTF1 levels in the absence of CDC14 prevent the firing of bivalent promoters required for differentiation. These results, along recent data suggesting a critical role for cell cycle kinases in pluripotency, suggest that cell cycle kinase-phosphatase modules such as CDK-CDC14 are critical for linking cell cycle regulation and self-renewal, with a specific function for CDC14 phosphatases modulating key epigenetic regulators during the terminal exit from pluripotency.
2022-10-31 | GSE196139 | GEO
Project description:CDC14 phosphatases are critical components of the cell cycle machinery that drives exit from mitosis in yeast. However, the two mammalian paralogs, CDC14A and CDC14B, are dispensable for cell cycle progression or exit, and their function remains unclear. By generating a double Cdc14a; Cdc14b -null mouse model, we report here that CDC14 phosphatases control cell differentiation in pluripotent cells, and their absence results in deficient development of the neural system. Lack of CDC14 impairs neural differentiation from embryonic stem cells (ESCs) accompanied by deficient induction of genes controlled by bivalent promoters. CDC14 directly dephosphorylates and destabilizes Undifferentiated embryonic Transcription Factor 1 (UTF1) during the exit from stemness. Multiomic single-cell analysis of differentiating ESCs suggest that increased UTF1 levels in the absence of CDC14 prevent the firing of bivalent promoters required for differentiation. These results, along recent data suggesting a critical role for cell cycle kinases in pluripotency, suggest that cell cycle kinase-phosphatase modules such as CDK-CDC14 are critical for linking cell cycle regulation and self-renewal, with a specific function for CDC14 phosphatases modulating key epigenetic regulators during the terminal exit from pluripotency.
2022-10-31 | GSE196137 | GEO
Project description:RIF1 is a multifunctional protein that plays key roles in the regulation of DNA processing. During repair of DNA double-strand breaks (DSBs), RIF1 functions in the 53BP1-Shieldin pathway that inhibits resection of DNA ends to modulate the cellular decision on which repair pathway to engage. Under conditions of replication stress, RIF1 protects nascent DNA at stalled replication forks from degradation by the DNA2 nuclease. How these RIF1 activities are regulated at the post-translational level has not yet been elucidated. Here, we identified a cluster of conserved ATM/ATR consensus SQ motifs within the intrinsically disordered region (IDR) of mouse RIF1 that are phosphorylated in proliferating B lymphocytes. We found that phosphorylation of the conserved IDR SQ cluster is dispensable for the inhibition of DSB resection by RIF1, but is essential to counteract DNA2-dependent degradation of nascent DNA at stalled replication forks. Therefore, our study identifies a key molecular feature that enables the genome-protective function of RIF1 during DNA replication stress.
2022-04-14 | PXD031972 | Pride
Project description:Temporal control over protein phosphorylation and dephosphorylation is crucial for accurate chromosome segregation and for completion of the cell division cycle during exit from mitosis. In budding yeast, the Cdc14 phosphatase is thought to be a major regulator at this time, while in higher eukaryotes PP2A phosphatases take a dominant role. Here, we use time-resolved phosphoproteome analysis in budding yeast to evaluate the respective contributions of Cdc14 and the two main PP2A isoforms, PP2A(Cdc55) and PP2A(Rts1). This reveals an overlapping requirement for all three phosphatases during mitotic progression. Cdc14 instructs the sequential pattern of phosphorylation changes, in part through its preferential recognition of serine-based cyclin-dependent kinase (Cdk) substrates. PP2A(Cdc55) and PP2A(Rts1) in turn exhibit a broad substrate spectrum with some selectivity for phospho-threonines and a role for PP2A(Rts1) in sustaining Aurora kinase activity. Our results illustrate synergy and coordination between phosphatases as they orchestrate phosphoproteome dynamics during mitotic progression.
2019-11-12 | PXD012860 | Pride