Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

DNA replication origins in regenerating mouse livers reveal features of genes and a role of ATR in aging

ABSTRACT: To help understand how the genome is replicated in mammals, we mapped genome-wide the sites of firing of DNA replication origins in regenerating livers of young and aged mice. In young mice, more than 3,500 origin firing sites were mapped. Monitoring of nascent transcription in vivo under the same conditions revealed that origins were associated with expressed genes, such that about half of all expressed genes had a DNA replication origin dedicated to replication of that gene; this origin could be located either upstream or downstream of the transcribed sequences. In aged mice, origins mapped to the same genomic sites, but firing was very inefficient and entry into S phase was accompanied by induction of a DNA damage response. Remarkably, inhibiting the replication stress checkpoint kinase ATR fully rescued origin firing in old mice, but also led to induction of an inflammatory response at later time points. We propose that genes may have evolved as replication-transcription units carrying their own dedicated replication origins and that suppression of origin firing in regenerating livers of aged mice is an active process mediated by the ATR checkpoint.

ORGANISM(S): Mus musculus

PROVIDER: GSE231430 | GEO | 2024/12/31

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

The TRESLIN-MTBP complex couples completion of DNA replication with S/G2 transition

Project description:It has been proposed that ATR kinase senses the completion of DNA replication to initiate the S/G2 transition. In contrast to this model, we show here that the TRESLIN-MTBP complex prevents a premature entry into G2 from early S-phase independently of ATR/CHK1 kinases. TRESLIN-MTBP acts transiently at pre-replication complexes (preRCs) to initiate origin firing and is released after the subsequent recruitment of CDC45. This dynamic behavior of TRESLIN-MTBP implements a monitoring system that checks the activation of replication forks and senses the rate of origin firing to prevent the entry into G2. This system detects the decline in the number of origins of replication that naturally occurs in very late S, which is the signature that cells use to determine the completion of DNA replication and permit the S/G2 transition. Our work introduces TRESLIN-MTBP as a key player in cell cycle control independent of canonical checkpoints.

2023-03-11 | PXD035353 | Pride

The TRESLIN-MTBP complex couples completion of DNA replication with S/G2 transition

2022-08-06 | GSE210129 | GEO

ATR kinase supports normal proliferation in the early S phase by preventing replication resource exhaustion [HTGTS]

Project description:The ATR kinase, which coordinates cellular responses to DNA replication stress, is also essential for the proliferation of normal unstressed cells. Although its role in the replication stress response is well defined, the mechanisms by which ATR supports normal cell proliferation remain elusive. Here, we show that Atr is dispensable for the viability of G0-arrested naïve B cells. However, upon cytokine-induced proliferation, Atr-deficient B cells initiate DNA replication efficiently in early S phase, but by mid-S phase they display dNTP depletion, fork stalling, and replication failure. Nonetheless, productive DNA replication can be restored in Atr-deficient cells by pathways that suppress origin firing, such as downregulation of CDC7 and CDK1 kinase activities. Together, these findings indicate that ATR supports the proliferation of normal unstressed cells by tempering the pace of origin firing during the early S phase to avoid exhaustion of dNTPs and other replication factors.

2022-12-31 | GSE212195 | GEO

ATR kinase supports normal proliferation in the early S phase by preventing replication resource exhaustion [RNA-seq]

2022-12-31 | GSE212194 | GEO

ATR kinase supports normal proliferation in the early S phase by preventing replication resource exhaustion [CRISPR-Cas9 gRNA screen]

2022-12-31 | GSE214643 | GEO

Quantitative BrdU immunoprecipitation method demonstrates that Fkh1 and Fkh2 are rate-limiting activators of replication origins that reprogram replication timing in G1 phase (BrdU)

Project description:The S. cerevisiae Forkhead Box (FOX) proteins, Fkh1 and Fkh2, regulate diverse cellular processes including transcription, long-range DNA interactions during homologous recombination, and replication origin timing and long-range origin clustering. As stimulators of early origin activation, we hypothesized that Fkh1 and Fkh2 abundance limits the rate of origin activation genome-wide. Existing methods, however, were not well suited to quantitative, genome-wide measurements of origin firing between strains and conditions. To overcome this limitation, we developed qBrdU-seq, a quantitative method for BrdU incorporation analysis of replication dynamics, and applied it to show that overexpression of Fkh1 and Fkh2 advance the initiation timing of many origins throughout the genome resulting in a higher total level of origin initiations in early S phase. The higher initiation rate is accompanied by slower replication fork progression, thereby maintaining a normal length of S phase without causing detectable Rad53 checkpoint kinase activation. The advancement of origin firing time, including that of origins in heterochromatic domains, was established in late G1 phase, indicating that origin timing can be reset subsequently to origin licensing. These results provide novel insights into the mechanisms of origin timing regulation by identifying Fkh1 and Fkh2 as rate-limiting factors for origin firing that determine the ability of replication origins to accrue limiting factors and have the potential to reprogram replication timing late in G1 phase. 5 total experiments with replicates

2015-12-18 | E-GEOD-71050 | biostudies-arrayexpress

Bubble-seq Analysis of the Human Genome Reveals Distinct Chromatin-Mediated Mechanisms for Regulating Early- and Late-Firing Origins

Project description:We have devised a method for isolating virtually pure and comprehensive libraries of restriction fragments that contained replication initiation sites (bubbles) in vivo (Mesner et al. 2009). We have now sequenced and mapped the bubble-containing fragments from GM06990, a near-normal EBV-transformed lymphoblastoid cell line, and have compared origin distributions to a comprehensive replication timing study recently published for this cell line. We find that early-firing origins overwhelmingly represent zones, associate only marginally with active transcription units, are localized within large domains of open chromatin, and are significantly associated with DNAseI hypersensitivity. Origin density falls from early- to mid-S-phase, but, surprisingly, rises again in late-S-phase to density levels only 17% lower than in early S-phase. Strikingly, late origin density calculated on the 1Mb scale is robustly correlated with measures of increasing chromatin compaction. While origin efficiency decreases with replication time, the median efficiency in late-replicating, heterochromatic domains is only 25% lower than in early-replicating, euchromatic loci. Thus, the activation of early- and late-firing origins must be regulated by quintessentially different mechanisms. The aggregate data can be unified into a model in which initiation site selection is driven almost entirely by epigenetic factors that fashion both the long-range and local chromatin environments, with underlying DNA sequence and local transcriptional activity playing only minor roles. Importantly, the comprehensive origin map we have prepared for GM06990 overlaps only modestly with origin maps recently reported for the genomes of four different human cell lines based on distributions of small nascent strands. 3 samples of DNA replication (2 technical replicates, 1 biological replicate), 2 samples of poly-A RNA-Seq

2013-07-09 | E-GEOD-38809 | biostudies-arrayexpress

Quantitative BrdU immunoprecipitation method demonstrates that Fkh1 and Fkh2 are rate-limiting activators of replication origins that reprogram replication timing in G1 phase (ChIP)

2015-12-18 | GSE71051 | GEO

Quantitative BrdU immunoprecipitation method demonstrates that Fkh1 and Fkh2 are rate-limiting activators of replication origins that reprogram replication timing in G1 phase (BrdU)

2015-12-18 | GSE71050 | GEO

Dbf4 recruitment by forkhead transcription factors defines an upstream rate-limiting step in determining replication origin firing

Project description:Initiation of eukaryotic chromosome replication follows a spatiotemporal program. Current model suggests that replication origins compete for a limited pool of initiation factors. However, it remains to be answered how these limiting factors are preferentially recruited to early origins. Here, we report that Dbf4 is enriched at early origins through its interaction with forkhead transcription factors Fkh1 and Fkh2. This interaction is mediated by Dbf4 C-terminus and was successfully reconstituted in vitro. An interaction defective mutant dbf4ΔC phenocopies fkh alleles in terms of origin firing. Remarkably, genome-wide replication profiles reveal that the direct fusion of the DNA-binding domain of Fkh1 to Dbf4 restores the Fkh-dependent origin firing, but specifically interferes with the pericentromeric origin activation. Furthermore, Dbf4 directly interacts with Sld3 and promotes the recruitment of downstream limiting factors. These data suggest that Fkh1 targets Dbf4 to a subset of non-centromeric origins to promote early replication, in a manner that is reminiscent to the recruitment of Dbf4 to pericentromeric origins by Ctf19.

2018-01-19 | GSE103073 | 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