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Overexpression of Claspin and Timeless protects cancer cells from replication stress in a checkpoint-independent manner

ABSTRACT: Overexpression of Claspin and Timeless protects cancer cells from replication stress in a checkpoint-independent manner

PROVIDER: PRJNA508601 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR8284460_1.fastq.gz	Fastqsanger.gz
	SRR8284460_2.fastq.gz	Fastqsanger.gz
	SRR8284461.fastq.gz	Fastqsanger.gz
	SRR8284461_1.fastq.gz	Fastqsanger.gz
	SRR8284461_2.fastq.gz	Fastqsanger.gz

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Similar Datasets

Overexpression of Claspin and Timeless protects cancer cells from replication stress in a checkpoint-independent manner.

Project description:Oncogene-induced replication stress (RS) promotes cancer development but also impedes tumor growth by activating anti-cancer barriers. To determine how cancer cells adapt to RS, we have monitored the expression of different components of the ATR-CHK1 pathway in primary tumor samples. We show that unlike upstream components of the pathway, the checkpoint mediators Claspin and Timeless are overexpressed in a coordinated manner. Remarkably, reducing the levels of Claspin and Timeless in HCT116 cells to pretumoral levels impeded fork progression without affecting checkpoint signaling. These data indicate that high level of Claspin and Timeless increase RS tolerance by protecting replication forks in cancer cells. Moreover, we report that primary fibroblasts adapt to oncogene-induced RS by spontaneously overexpressing Claspin and Timeless, independently of ATR signaling. Altogether, these data indicate that enhanced levels of Claspin and Timeless represent a gain of function that protects cancer cells from of oncogene-induced RS in a checkpoint-independent manner.

| S-EPMC6385232 | biostudies-literature

Overexpression of Claspin and Timeless protects cancer cells from replication stress in a checkpoint-independent manner

Project description:RNA-seq analysis of BJ cells overexpressing RasV12 and escaping senescence

2018-12-07 | GSE123380 | GEO

Separable functions of Tof1/Timeless in intra-S-checkpoint signalling, replisome stability and DNA topological stress

Project description:The highly conserved Tof1/Timeless proteins minimise replication stress and promote normal DNA replication. They are required to mediate the DNA replication checkpoint (DRC), the stable pausing of forks at protein fork blocks, the coupling of DNA helicase and polymerase functions during replication stress (RS) and the preferential resolution of DNA topological stress ahead of the fork. Here we demonstrate that the roles of the Saccharomyces cerevisiae Timeless protein Tof1 in DRC signalling and resolution of DNA topological stress require distinct N and C terminal regions of the protein, whereas the other functions of Tof1 are closely linked to the stable interaction between Tof1 and its constitutive binding partner Csm3/Tipin. By separating the role of Tof1 in DRC from fork stabilisation and coupling, we show that Tof1 has distinct activities in checkpoint activation and replisome stability to ensure the viable completion of DNA replication following replication stress.

2020-10-08 | GSE144321 | GEO

The replication checkpoint protects fork stability by releasing transcribed genes from nuclear pores.

Project description:Transcription hinders replication fork progression and stability, and the Mec1/ATR checkpoint protects fork integrity. Examining checkpoint-dependent mechanisms controlling fork stability, we find that fork reversal or dormant origin firing owing to checkpoint defects are rescued in checkpoint mutants lacking THO, TREX-2 or inner basket nucleoporins. Gene gating tethers transcribed genes to the nuclear periphery and is counteracted by checkpoint kinases through phosphorylation of nucleoporins such as Mlp1. Checkpoint mutants fail to detach transcribed genes from nuclear pores, thus generating topological impediments for incoming forks. Releasing this topological complexity by introducing a double-strand break between a fork and a transcribed unit prevents fork collapse. Mlp1 mutants mimicking constitutive checkpoint-dependent phosphorylation also alleviate checkpoint defects. We propose that the checkpoint assists fork progression and stability at transcribed genes by phosphorylating key nucleoporins and counteracting gene gating, thus neutralizing the topological tension generated at nuclear pore gated genes.

2011-07-22 | GSE30024 | GEO

Timeless collaborates with DDX11 to ensure processive replication of G4-forming DNA [RNA-seq]

Project description:Regions of DNA with the potential to form secondary structure pose a frequent and significant impediment to DNA replication that must be actively countered by cells in order to preserve genetic and epigenetic integrity. The fork protection complex (FPC), a conserved group of replisome-associated proteins, comprising Timeless, plays an important role in maintaining efficient replisome function. A previously unappreciated DNA binding domain in the C terminus of Timeless, which exhibits specificity towards G4 structures, acts in collaboration with the DDX11 helicase to ensure replication of G4 structures in vivo and maintenance of genetic and epigenetic stability. Using RNA-seq experiments, we show that (i) Timeless and DDX11 share common gene targets, (ii) the promoter of Timeless- and DDX11-dependent genes are enriched in G4 structures in the vicinity of their promoter and (iii) both Timeless and DDX11 share a common set of gene targets with the FANCJ helicase known to maintain epigenetic stability in the vicinity of G4 structures.

2020-07-01 | GSE139256 | GEO

Separable functions of Tof1/Timeless in intra-S-checkpoint signalling, replisome stability and DNA topological stress

Project description:Separable functions of Tof1/Timeless in intra-S-checkpoint signalling, replisome stability and DNA topological stress

| PRJNA603364 | ENA

Circadian protein TIMELESS regulates synaptic plasticity and memory by modulating cAMP signaling

Project description:Regulation of neurons by circadian clock genes is thought to contribute to the maintenance of neuronal functions that ultimately underlie animal behavior. However, the impact of circadian genes on cellular and molecular mechanisms that influnce synaptic plasticity and cognitive function remain to be identified. Here, we show that conditional deletion of the circadian gene Timeless in the adult forebrain leads to an impairment in working and fear memory in mice. These cognitive phenotypes were accompanied with LTP attenuation of hippocampal Schaffer-collateral synapses. We discovered TIMELESS protein acts as a transcriptional factor regulating phosphodiesterase 4B (PDE4B) expression. Through Pde4b transcription, TIMELESS negatively regulates cAMP signaling to modulate AMPA receptor GluA1 function and fine-tune synaptic plasticity. Our data provide insights into the neuron-specific function of mammalian TIMELESS by defining a mechanism that regulates synaptic plasticity and cognitive function.

2023-04-17 | GSE208149 | GEO

Transcription profiling of replication checkpoint response in fission yeast

Project description:Transcription profiling of replication checkpoint response in fission yeast.

2008-11-15 | E-MEXP-1902 | biostudies-arrayexpress

DNA replication and DSB factor binding in the meiotic S-phase checkpoint in budding yeast

Project description:During gamete formation, crossover recombination must occur on replicated DNA to ensure proper chromosome segregation in the first meiotic division. We identified a Mec1/ATR-dependent replication checkpoint in budding yeast that prevented the earliest stage of recombination, the programmed induction of DNA double-strand breaks (DSBs), when pre-meiotic DNA replication was delayed. The checkpoint suppressed DSBs through three complementary mechanisms: inhibition of Mer2 phosphorylation by Dbf4-dependent Cdc7 kinase, preclusion of chromosomal loading of Rec114 and Mre11, and lowered abundance of the Spo11 nuclease. Without this checkpoint, cells formed DSBs on partially replicated chromosomes. Importantly, such DSBs frequently failed to be repaired and impeded further DNA synthesis, leading to a rapid loss in cell viability. We conclude that a checkpoint-dependent constraint of DSB formation to duplicated DNA is critical not only for meiotic chromosome assortment, but also to protect genome integrity during gametogenesis. DSB factor association was measured in wild-type and checkpoint mutants strains under non-inducing or replication checkpoint inducing conditions. Additionally, DNA replication and helicase loading were measured in a replication and checkpoint deficient strain (cdc6-mn).

2013-09-20 | E-GEOD-46841 | biostudies-arrayexpress

Type 1 Diabetes DNA Damage Checkpoint Pathway Quantitation

Project description:iTRAQ-based quantitative proteomics and phosphoproteomics analyses of induced pluripotent stem cells (iPSC) from patients with longstanding type 1 diabetes. "Preserved DNA Damage Checkpoint Pathway Protects From Complications in Long-standing Type 1 Diabetes", Cell Metabolism, in press.

2015-07-08 | MSV000079185 | MassIVE

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