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Conservation of replication timing reveals global and local regulation of replication origin activity.

ABSTRACT: DNA replication initiates from defined locations called replication origins; some origins are highly active whereas others are dormant and rarely used. Origins also differ in their activation time resulting in particular genomic regions replicating at characteristic times and in a defined temporal order. Here we report the comparison of genome replication in four budding yeast species: Saccharomyces cerevisiae, S. paradoxus, S. arboricolus and S. bayanus. First, we find that the locations of active origins are predominantly conserved between species, whereas dormant origins are poorly conserved. Second, we generated genome-wide replication profiles for each of these species and discovered that the temporal order of genome replication is highly conserved. Therefore, active origins are not only conserved in location, but also activation time. Only a minority of these conserved origins show differences in activation time between these species. To gain insight as to the mechanisms by which origin activation time is regulated we generated replication profiles for a S. cerevisiae / S. bayanus hybrid strain and find that there are both local and global regulators of origin function.

ORGANISM(S): Saccharomyces bayanus Saccharomyces bayanus x Saccharomyces cerevisiae Saccharomyces cerevisiae Saccharomyces arboricola Saccharomyces paradoxus

PROVIDER: GSE36045 | GEO | 2012/06/19

SECONDARY ACCESSION(S): PRJNA151773

REPOSITORIES: GEO

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Conservation of replication timing reveals global and local regulation of replication origin activity.

Project description:DNA replication initiates from defined locations called replication origins; some origins are highly active whereas others are dormant and rarely used. Origins also differ in their activation time resulting in particular genomic regions replicating at characteristic times and in a defined temporal order. Here we report the comparison of genome replication in four budding yeast species: Saccharomyces cerevisiae, S. paradoxus, S. arboricolus and S. bayanus. First, we find that the locations of active origins are predominantly conserved between species, whereas dormant origins are poorly conserved. Second, we generated genome-wide replication profiles for each of these species and discovered that the temporal order of genome replication is highly conserved. Therefore, active origins are not only conserved in location, but also activation time. Only a minority of these conserved origins show differences in activation time between these species. To gain insight as to the mechanisms by which origin activation time is regulated we generated replication profiles for a S. cerevisiae / S. bayanus hybrid strain and find that there are both local and global regulators of origin function. Measurement of genome replication time from 4 budding yeast species (Saccharomyces cerevisiae, S. paradoxus, S. arboricolus and S. bayanus) and a hybrid (between Saccharomyces cerevisiae and S. bayanus). For each strain two samples were analysed: a replicating sample (from S phase) and a non-replicating sample (from G2 phase) The reference genome sequences for each yeast species are available as Series supplementary file [sac*.fa]

2012-06-19 | E-GEOD-36045 | biostudies-arrayexpress

Convergence of SIRT1 and ATR signaling to modulate replication origin dormancy

Project description:During routine genome duplication, many potential replication origins remain inactive, or dormant. Such origin dormancy is achieved, in part, by an interaction with the metabolic sensor SIRT1 deacetylase. We report here that dormant origins are a group of consistent, pre-determined genomic sequences that can be distinguished from baseline (i.e. ordinarily active) origins by their preferential association with MCM2, a component of the replicative helicase, phosphorylated on serine 108 (pS108-MCM2). pS108-MCM2 is a substrate of the ATR kinase, which is recruited to chromatin via an interaction with hyperacetylated TOPBP1 in cells undergoing replication stress or in cells devoid of SIRT1 deacetylase activity. In turn, S108-MCM2 phosphorylation enhances a second, DDK-dependent, S139-MCM2 phosphorylation, which triggers initiation of DNA replication at dormant origins. These observations suggest that replication origin dormancy and activation are regulated by distinct post-translational modifications on the MCM helicase that reflect a balance between SIRT1 activity and ATR signaling.

| MSV000088134 | MassIVE

Phosphorylated SIRT1 associates with replication origins to prevent excess replication initiation and preserve genomic stability

Project description:Chromatin structure affects DNA replication patterns, but the role of specific chromatin modifiers in regulating the replication process is yet unclear. We report that phosphorylation of the human SIRT1 deacetylase on Threonine 530 (T530-pSIRT1) modulates DNA synthesis. T530-pSIRT1 associates with replication origins and inhibits replication from a group of ÒdormantÓ potential replication origins, which initiate replication only when cells are subject to replication stress. Although both active and dormant origins bind T530-pSIRT1, active origins are distinguished from dormant origins by their unique association with an open chromatin mark, histone H3 methylated on lysine 4. SIRT1 phosphorylation also facilitates leading and lagging strand coordination. SIRT1 T530 phosphorylation is essential to prevent DNA breakage upon replication stress and cells harboring SIRT1 that cannot be phosphorylated exhibit a high prevalence of extrachromosomal elements, hallmarks of perturbed replication. These observations suggest that SIRT1 phosphorylation modulates the distribution of replication initiation events to insure genomic stability.

2017-06-02 | GSE94403 | GEO

Convergence of SIRT1 and ATR signaling to modulate replication origin dormancy

Project description:During routine genome duplication, many potential replication origins remain inactive, or 'dormant'. Such origin dormancy is achieved, in part, by an interaction with the metabolic sensor SIRT1 deacetylase. We report here that dormant origins are a group of consistent, pre-determined genomic sequences that can be distinguished from baseline (i.e. ordinarily active) origins by their preferential association with MCM2, a component of the replicative helicase, phosphorylated on serine 108 (pS108-MCM2). pS108-MCM2 is a substrate of the ATR kinase, which is recruited to chromatin via an interaction with hyperacetylated TOPBP1 in cells undergoing replication stress or in cells devoid of SIRT1 deacetylase activity. In turn, S108-MCM2 phosphorylation enhances a second, DDK-dependent, S139-MCM2 phosphorylation, which triggers initiation of DNA replication at dormant origins. These observations suggest that replication origin dormancy and activation are regulated by distinct post-translational modifications on the MCM helicase that reflect a balance between SIRT1 activity and ATR signaling.

2022-05-09 | GSE184353 | GEO

Rif1 binds to G-quadruplexes and suppresses replication over a long distances

Project description:Rif1 regulates replication timing and repair of double-stranded DNA breaks. Using Chromatin-immunoprecipitation-Sequencing method, we have identified 35 high-affinity Rif1 binding sites in fission yeast chromosomes. Binding sites, preferentially located to the vicinity of dormant origins, tended to contain at least two copies of a conserved motif, CNWWGTGGGGG, and base substitution within these motifs resulted in complete loss of Rif1 binding and activation of late-firing or dormant origins located as far as 50 kb away. We show that Rif1 binding sites adopt G-quadruplex-like structures in vitro in a manner dependent on the conserved sequence as well as on other G-tracts, and that the purified Rif1 preferentially binds to this structure. These results suggest that Rif1 recognizes and binds to G-quadruplex-like structures at selected intergenic regions to generate local chromatin structures that may exert a long-range suppressive effects on origin firing. ChIP-Seq profiles of Rif1 and DNA replicaiton (BrdU-incorporation) vs Input in wildt type, rap1∆, taz1∆, Rif1BS mutants and rif1∆

2015-09-10 | E-GEOD-65293 | biostudies-arrayexpress

SIRT1 prevents R-loops during chronological aging by modulating DNA replication at rDNA loci

Project description:In metazoans, the largest sirtuin, SIRT1, is a nuclear protein implicated in epigenetic modifications, circadian signaling, DNA recombination, replication and repair. Our previous studies have demonstrated that SIRT1 binds replication origins and inhibits replication initiation from a group of potential initiation sites (dormant origins). We studied the effects of aging and SIRT1 activity on replication origin usage and the incidence of transcription-replication collisions (creating R-loop structures) in adult human cells obtained at different time points during chronological aging and in cancer cells. In primary, untransformed cells, SIRT1 activity declined, and the prevalence of R-loops rose with chronological aging. Both the reduction of SIRT1 activity and the increased abundance of R-loops were also observed during the passage of primary cells in culture. All cells, regardless of donor age or transformation status, reacted to short-term, acute chemical inhibition of SIRT1 with the activation of excessive replication initiation events coincident with an increased prevalence of R-loops. However, only cancer cells showed genome-wide activation of dormant origins during long-term proliferation with mutated or depleted SIRT1, whereas in primary cells, aging-associated SIRT1-mediated activation of dormant origins was restricted to rDNA loci. These observations suggest that chronological aging and the associated decline in SIRT1 activity relaxes the regulatory networks that protect cells against excess replication and that the mechanisms protecting from replication-transcription collisions at the rDNA loci manifest as a differentially enhanced sensitivity to SIRT1 decline and chronological aging.

2023-11-27 | GSE247469 | GEO

Rif1 binds to G-quadruplexes and suppresses replication over a long distances

2015-09-10 | GSE65293 | GEO

Rif1 is a global regulator of timing of replication origin firing in fission yeast

Project description:One of the long-standing questions in eukaryotic DNA replication is the mechanisms that determine where and when a particular segment of the genome is replicated. Cdc7/Hsk1 is a conserved kinase required for initiation of DNA replication, and may affect the site selection and timing of origin firing. We identified rif1∆, a null mutant of rif1+, a conserved telomere binding factor, as an efficient bypass mutant of fission yeast hsk1. Extensive deregulation of dormant origins over a wide range of the chromosomes occurs in rif1∆ in the presence or absence of HU. At the same time, many early-firing, efficient origins are suppressed or delayed in firing timing in rif1∆. Rif1 binds not only to telomeres but also to many specific locations on the arm segments that only partially overlap with the pre-Replicative Complex assembly sites, although Rif1 tends to bind in the vicinity of the late/ dormant origins activated in rif1∆. The binding to the arm segments occurs through M to G1 phase in a manner independent of Taz1 and appears to be essential for the replication timing program during normal cell cycle. Our data demonstrate that Rif1 is a critical determinant of origin activation program on the fission yeast chromosomes. BrdU incorporation profiles at early S-phase in Wild vs rif1∆. Cdc45 binding profiles at early S-phase in Wild vs rif1∆. Rif1 binidng sites aroud G1/S boudary and at M-phase. Mcm4 binding sites in wild, hsk1-89 temperature mutant and rif1∆.

2011-12-13 | GSE34369 | GEO

Transcriptionally Driven DNA Replication Programme of the Human Parasite Leishmania major

Project description:Faithful inheritance of the large eukaryotic genomes requires the orchestrated activation of multiple DNA replication origins. Although origin activation is mechanistically conserved among eukaryotes, how replication origins are specified and selected for activation in each S-phase seem to differ across the model systems studied. Here we provide a complete analysis of the nucleosomal landscape and replication programme of the human parasite Leishmania major, building on a better evolutionary understanding of replication organization in Eukarya. We found that active transcription is a driving force for the nucleosomal organization of L. major genome, and that both the spatial and the temporal programme of DNA replication can be explained as associated to RNA polymerase kinetics, without the need to invoke specific regulatory mechanisms. This simple scenario likely provides these organisms with the flexibility and robustness to deal with the continuous environmental changes that impose alterations in their genetic programmes during their parasitic life cycle stages. Our findings also suggest that coupling replication initiation to transcription elongation could be an ancient solution used by eukaryotic cells for origin maintenance Replication intitiation sites were defined using two replicates of short nascent strands of increasing sizes (F4 and F5) purified through three rounds of Lambda-exonuclease digestion, and a genomic DNA control (Ctrl). Nucleosome landscape was determined using two replicates of mononucleosomal-DNA derived from MNase-digested chromatin

2016-06-10 | E-GEOD-81991 | biostudies-arrayexpress

Evolution of Replication Origins in Vertebrate Genomes: Rapid Turnover Despite Selective Constraints [SNS-seq]

Project description:Background: The replication program of vertebrate genomes is driven by the chromosomal distribution and timing of activation of ten of thousands replication origins. Genome-wide studies have shown the frequent association of origins with promoters and CpG islands, and their enrichment in G-quadruplexes sequence motifs (G4). However the genetic determinants driving their activity remain poorly understood. To gain insight on functional constraints operating on replication origins and on their spatial distribution, we conduct the first evolutionary comparison of genome-wide origins maps across vertebrates. Results: We generated a high resolution genome-wide map of chicken replication origins (the first of a bird genome), and performed an extensive comparison with human and mouse maps. The analysis of intra-species polymorphism revealed a strong depletion of genetic diversity on a ∼ 40bp region centered on the replication initiation loci. Surprisingly, this depletion in genetic diversity is not linked to the presence of G4 motifs, nor to the association with promoters or CpG islands. In contrast, we also show that origins have experienced a rapid turnover during vertebrates evolution, since pairwise comparisons of origin maps revealed that only 4 to 24% of them are conserved between any two species. Conclusions: This study unravels the existence of a novel genetic determinant of replication origins, whose precise functional role remains to be determined. Despite the importance of replication initiation activity for the fitness of organisms, the distribution of replication origins along vertebrate chromosomes is highly flexible.

2019-03-06 | GSE119488 | GEO

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