Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA345510 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR4348870.fastq.gz | Fastqsanger.gz | |||
| SRR4348871.fastq.gz | Fastqsanger.gz | |||
| SRR4348862.fastq.gz | Fastqsanger.gz | |||
| SRR4348872.fastq.gz | Fastqsanger.gz | |||
| SRR4348863.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 15 |
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Project description:p53 induces cell death upon DNA damage, but this may not confer all of its tumor suppressor activity. We report that p53 activation enhances the processivity of DNA replication, as monitored by multi-label fiber assays, whereas removal of p53 reduces fork progression. This was observed in tumor-derived U2OS cells, but also in murine embryonic fibroblasts with heterozygous or homozygous p53 deletion, and in freshly isolated thymocytes from mice with differential p53 status. Mdm2, a p53-inducible gene product, similarly supported DNA replication even in p53-deficient cells, suggesting that sustained Mdm2-expression is at least one of the mechanisms allowing p53 to prevent replicative stress. Thus, p53 helps to protect the genome during S phase, by preventing the occurrence of stalled or collapsed replication forks. These results expand p53’s tumor-suppressive functions, adding to the ex-post model (elimination of damaged cells) an ex-ante activity, i.e. the prevention of DNA damage during replication.
2016-10-06 | GSE87668 | GEO
Project description:DNA polymerase epsilon (Pole) carries out leading strand synthesis with high fidelity owing to its exonuclease activity. Pole polymerase and exonuclease activities are in balance, due to partitioning of nascent strands between catalytic sites, so that net end resection occurs when synthesis is impaired. Stalling of chromosomal DNA synthesis activates replication checkpoint kinases, required to preserve the functional integrity of replication forks. We found that Pole is phosphorylated in a Rad53CHK1-dependent manner upon fork stalling, likely to limit Pole-driven nascent strand resection that causes replication fork collapse. In stress conditions Pole phosphorylation occurs on serine 430 of the Pol2 catalytic subunit. A S430 phosphomimic limits strand partitioning and exonucleolytic processivity, while non-phosphorylatable Pol2-S430A bypasses checkpoint regulation causing stalled fork resection and collapse. We propose that checkpoint kinases switch Pole to an exonuclease-safe mode by curbing active site partitioning thus preventing nascent strand resection and stabilizing stalled replication forks.
2021-04-30 | GSE156480 | GEO
Project description:Analysis of topoisomerase function in bacterial replication fork movement: use of DNA microarrays. We used DNA microarrays of the Escherichia coli genome to trace the progression of chromosomal replication forks in synchronized cells. We found that both DNA gyrase and topoisomerase IV (topo IV) promote replication fork progression. When both enzymes were inhibited, the replication fork stopped rapidly. The elongation rate with topo IV alone was 1/3 of normal. Genetic data confirmed and extended these results. Inactivation of gyrase alone caused a slow stop of replication. Topo IV activity was sufficient to prevent accumulation of (+) supercoils in plasmid DNA in vivo, suggesting that topo IV can promote replication by removing (+) supercoils in front of the chromosomal fork. This study is detailed in Khodursky AB et al.(2000) Proc Natl Acad Sci U S A 97:9419-24 Keywords: other
2001-07-30 | E-GEOD-8 | biostudies-arrayexpress
Project description:p53 is a major tumor suppressor gene that is frequently inactivated in human cancers. One prominent suppressive function of p53 is executing cell cycle arrest, senescence and apoptosis upon stress. Importantly, p53 loss is a prerequisite for cancer development, as is evident in Li-Fraumeni patients and p53 knockout mice. Here we investigated the effect of p53-loss, without induction of additional stress, on DNA replication and genomic instability. We revealed that p53 deficiency leads to enhanced proliferation without upregulating essential pathways requited to support normal DNA replication. This uncoordinated S-phase entry leads to replication-induced genomic instability. Interestingly, DNA replication analyses revealed a novel and non-classical form of replication stress induced by p53-loss, characterized by reduced fork rate progression without the compensation of dormant origin activation. Altogether, the results reveal a non-canonical tumor suppressive role of p53 in regulating DNA replication which safeguards genomic stability, underlying cancer predisposition induced by p53-loss. In order to understand the molecular basis for shp53 non-classical form of replication stress and replication-induced genomic instability, we performed unbiased whole transcriptome analysis of BJ-hTERT control cells in comparison to BJ-hTERT cells expressing shRNA against p53. Our results suggest that shp53 cells fail to upregulate essential pathways required for normal DNA replication.
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Project description:DNA replication fork speed, which controls the rate of genome duplication, has emerged as a key regulator of cellular plasticity. However, its role in neurogenesis remains unexplored. Mini-chromosome maintenance complex (MCMs)-binding protein (MCMBP) functions as a chaperone for newly synthesized MCMs, increasing chromatin coverage to restrain fork speed. We demonstrate that selective deletion of MCMBP in neural progenitor radial glial cells (RGCs) accelerates fork speed, triggering widespread apoptosis, DNA damage, and micronuclei formation, ultimately activating p53 and causing microcephaly. Unexpectedly, concurrent deletion of Trp53 and Mcmbp further increased fork speed, leading to extensive RGC detachment from the ventricular zone and acquisition of outer-RGC characteristics. Mechanistically, we found that the MCM3 subunit coordinates DNA and centrosome duplication, thereby mediating RGC attachment. Behavioral analysis revealed that disruption of fork speed results in anxiety-like behavior in mice. These findings unveil a previously unrecognized role for replication fork speed in neurogenesis.
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Project description:Analysis of topoisomerase function in bacterial replication fork movement: use of DNA microarrays. We used DNA microarrays of the Escherichia coli genome to trace the progression of chromosomal replication forks in synchronized cells. We found that both DNA gyrase and topoisomerase IV (topo IV) promote replication fork progression. When both enzymes were inhibited, the replication fork stopped rapidly. The elongation rate with topo IV alone was 1/3 of normal. Genetic data confirmed and extended these results. Inactivation of gyrase alone caused a slow stop of replication. Topo IV activity was sufficient to prevent accumulation of (+) supercoils in plasmid DNA in vivo, suggesting that topo IV can promote replication by removing (+) supercoils in front of the chromosomal fork. This study is detailed in Khodursky AB et al.(2000) Proc Natl Acad Sci U S A 97:9419-24 Keywords: other
2001-07-30 | GSE8 | GEO
Project description:To ensure efficient genome duplication, cells have evolved a multitude of factors that promote unperturbed DNA replication, and protect, repair and restart damaged forks. Here we identify DONSON as a novel fork protection factor, and report biallelic DONSON mutations in individuals with microcephalic dwarfism. We demonstrate that DONSON is a component of the replisome that stabilises forks during normal genome replication. Loss of DONSON leads to severe replication-associated DNA damage arising from nucleolytic cleavage of stalled replication forks. Furthermore, ATR-dependent ,signalling in response to replication stress is impaired in DONSON-deficient cells, resulting in decreased checkpoint activity, and potentiating chromosomal instability. Hypomorphic mutations substantially reduce DONSON protein levels and impair fork stability in patient cells, consistent with defective DNA replication underlying the disease phenotype In summary, we identify mutations in DONSON as a common cause of microcephalic dwarfism, and establish DONSON as a critical replication fork protein required for mammalian DNA replication and genome stability
2017-03-28 | MSV000080704 | MassIVE
Project description:The fork protection complex (FPC), composed of Mrc1, Tof1, and Csm3, supports rapid and stable DNA replication. Here, we show that FPC activity also introduces DNA damage by increasing DNA topological stress during replication. Mrc1 action increases DNA topological stress during plasmid replication, while Mrc1 or Tof1 activity causes replication stress and DNA damage within topologically constrained regions. We show that the recruitment of Top1 to the fork by Tof1 suppresses the DNA damage generated in these loci. While FPC activity introduces some DNA damage due to increased topological stress, the FPC is also necessary to prevent DNA damage in long replicons across the genome, indicating that the FPC is required for complete and faithful genome duplication. We conclude that FPC regulation must balance ensuring full genome duplication through rapid replication with minimizing the consequential DNA topological stress-induced DNA damage caused by rapid replication through constrained regions.
2024-10-21 | GSE239965 | GEO
Project description:We show that ligation-competent Okazaki fragments in Saccharomyces cerevisiae are sized according to the chromatin repeat. Using deep sequencing, we demonstrate that ligation junctions preferentially occur around nucleosome midpoints rather than in internucleosomal linker regions. Disrupting chromatin assembly or lagging strand polymerase processivity impacts both the size and the distribution of Okazaki fragments, suggesting a role for nascent chromatin, assembled immediately after the passage of the replication fork, in the termination of lagging strand synthesis. Our studies represent the first high-resolution analysis of eukaryotic Okazaki fragments in vivo, and establish a mechanistic link between the fundamental processes of DNA replication and chromatin assembly. 4 samples: replicate samples of wild-type and pol32 knockout
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Project description:SPO11-promoted DNA double-strand breaks (DSBs) formation is a crucial step for meiotic recombination, and it is indispensable to detect the broken DNA ends accurately for dissecting the molecular mechanisms behind. Here, we report a novel technique, named DEtail-seq (DNA End tailing followed by sequencing), that can directly and quantitatively capture the meiotic DSB 3’ overhang hotspots at single-nucleotide resolution.
2023-01-08 | GSE154227 | GEO