Selective interactions at pre-replication complexes categorize baseline and dormant origins
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1159299 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR30626800.fastq.gz | Fastqsanger.gz | |||
| SRR30626801.fastq.gz | Fastqsanger.gz | |||
| SRR30626801_1.fastq.gz | Fastqsanger.gz | |||
| SRR30626801_2.fastq.gz | Fastqsanger.gz | |||
| SRR30626802.fastq.gz | Fastqsanger.gz |
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Project description:The initiation of DNA synthesis in metazoans is restricted to a group of baseline replication origins, whereas other (dormant) origins do not initiate replication despite recruiting apparently indistinguishable pre-replication complexes. Dormant origins are activated as backups when DNA synthesis stalls. We report that dormant origins selectively bind CDK-phosphorylated RecQL4 (pRecQL4), a helicase mutated in Rothmund-Thomson, RAPADILINO and Baller-Gerold syndromes. In unperturbed cells, pRecQL4 restricts replication initiation to baseline origins by preventing dormant origins from binding the essential initiation factor MTBP. When cells encounter replication stress, pRecQL4 first promotes the dissociation of MTBP from chromatin, and then enables its redistribution to both baseline and dormant origins, facilitating compensatory initiation to complete genome duplication. Thus, MTBP-pRecQL4 interactions modulate replication origin choice and facilitate recovery from replication stress.
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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.
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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.
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Project description:BRCA2 is a tumor suppressor protein responsible for safeguarding the cellular genome from genotoxicity and replication stress, but the mechanism(s) by which this is achieved remains elusive. Here, we provide evidence that BRCA2 acts as a critical suppressor of “head-on” transcription-replication conflicts (HO-TRCs). Using Okazaki-fragment sequencing (Ok-seq) and computational analysis, we identified new origins (dormant origins) that are activated near the transcription termination sites (TTS) of highly expressed, long genes in response to replication stress. Dormant origins are a source for HO-TRCs, and drug treatments that inhibit dormant origin firing led to a reduction in HO-TRCs, R-loop formation, and DNA damage. Using super-resolution microscopy, we showed that HO-TRC events track with elongating RNA polymerase II, but not with transcription initiation. Importantly, RNaseH2 is recruited to sites of HO-TRCs in a BRCA2-dependent manner to help alleviate toxic R-loops associated with HO-TRCs. Collectively, our results identify a new source of genomic instability caused by HO-TRCs in BRCA2-deficient ovarian cancer precursor cells, providing a new strategy in modulating HO-TRCs to enhance genomic instability
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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.
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Project description:Evolution of Replication Origins in Vertebrate Genomes: Rapid Turnover Despite Selective Constraints [SNS-seq]
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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