Replication stress affects epigenetic stability
Ontology highlight
ABSTRACT:
ORGANISM(S): Schizosaccharomyces pombe
PROVIDER: GSE89816 | GEO | 2017/08/18
SECONDARY ACCESSION(S): PRJNA353373
REPOSITORIES: GEO
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Project description:Camptothecin-Induced Replication Stress Affects DNA Replication Profiling by E/L Repli-Seq
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Project description:H3K9me2 profiles and Fft3 occupancy in fission yeast. Heterochromatin can be epigenetically inherited in cis, leading to stable maintenance of gene expression states. However, the mechanisms underlying heterochromatin inheritance remain unclear. Here we identify Fft3, a homolog of the mammalian SMARCAD1 Snf2 chromatin remodeler, as a factor uniquely required for heterochromatin inheritance, rather than for de novo assembly. Importantly, we find that Fft3 bound to heterochromatic loci suppresses turnover of parental histones and is critical for the epigenetic transmission of heterochromatin in cycling cells. Surprisingly, Fft3 also localizes to several euchromatic loci where it is required for proper replication progression. Fft3 promotes nucleosome stability at these loci to prevent R-loop formation that can impede replication machinery. Strikingly, overexpression of the Clr4/Suv39h methyltransferase, which is also required for efficient replication through these loci, suppresses phenotypes associated with the loss of Fft3. Thus, we find that Fft3 promotes nucleosome stability to facilitate heterochromatin inheritance and also acts in parallel to Clr4 ensure proper replication of euchromatic regions.
2017-03-21 | GSE88902 | GEO
Project description:E/L Repli-seq is a powerful tool for detecting cell type-specific replication landscapes in mammalian cells, but its potential to monitor DNA replication under replication stress awaits better understanding. Here, we used E/L Repli-seq to examine the temporal order of DNA replication in human retinal pigment epithelium cells treated with the topoisomerase I inhibitor camptothecin. We found that the replication profiles by E/L Repli-seq exhibits characteristic patterns after replication-stress induction, including the loss of specific initiation zones within individual early replicating timing domains. We also observed global disappearance of the replication timing domain structures in the profiles, which can be explained by checkpoint-dependent suppression of replication initiation. Thus, our results demonstrate the effectiveness of E/L Repli-seq at identifying cells with replication-stress-induced altered DNA replication programs.
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Project description:The fidelity of epigenetic inheritance or, the precision by which epigenetic information is passed along, is an essential parameter for measuring the effectiveness of the process. How the precision of the process is achieved or modulated, however, remains largely elusive. We have performed quantitative measurement of epigenetic fidelity, using position effect variegation (PEV) in Schizosaccharomyces pombe as readout, to explore whether replication perturbation affects nucleosome-mediated epigenetic inheritance. We show that replication stresses, due to either hydroxyurea treatment or various forms of genetic lesions of the replication machinery, reduce the inheritance accuracy of CENP-A/Cnp1 nucleosome positioning within centromere. Mechanistically, we demonstrate that excessive formation of single-stranded DNA, a common molecular abnormality under these conditions, might have correlation with the reduction in fidelity of centromeric chromatin duplication. Furthermore, we show that replication stress broadly changes chromatin structure at various loci in the genome, such as telomere heterochromatin expanding and mating type locus heterochromatin spreading out of the boundaries. Interestingly, the levels of inheritable expanding at sub-telomeric heterochromatin regions are highly variable among independent cell populations. Finally, we show that HU treatment of the multi-cellular organisms C. elegans and D. melanogaster affects epigenetically programmed development and PEV, illustrating the evolutionary conservation of the phenomenon. Replication stress, in addition to its demonstrated role in genetic instability, promotes variable epigenetic instability throughout the epigenome.
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Project description:Structurally complex genomic regions, such as centromeres, are inherently difficult to duplicate. The mechanism that underlies centromere inheritance is not well understood, and one of the key questions relates to the reassembly of centromeric chromatin following DNA replication. Here we define the SNF2 ATPase ERCC6L2 as a key regulator of this process. ERCC6L2 accumulates at centromeres and promotes efficient deposition of core centromeric factors. Our genomic analyses show that ERCC6L2 deficiency erodes centromeric chromatin, leading to unrestrained replication of centromeric DNA. We also establish that, beyond centromeres, ERCC6L2 facilitates replication at genomic repeats and non-canonical DNA structures. Notably, ERCC6L2 interacts with the major DNA replication factor PCNA through an atypical peptide, presented here as a co-crystal structure. Finally, we examine ERCC6L2 activities at DNA breaks, and show that it acts to restrict end resection independently of the 53BP1-REV7-Shieldin complex. Our observations allow us to propose a mechanistic model of ERCC6L2 activity, which reconciles its seemingly distinct functions in DNA repair and DNA replication. Together, these findings provide a new molecular context for studies linking ERCC6L2 to human disease.
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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:The influence of mono-ubiquitylation of histone H2B (H2Bub) on transcription via nucleosome reassembly has been widely documented. Recently, it has also been shown that H2Bub promotes recovery from replication stress; however, the underling molecular mechanism remains unclear. Here, we show that H2B ubiquitylation coordinates activation of the intra-S replication checkpoint and chromatin re-assembly, in order to limit fork progression and DNA damage in the presence of replication stress. In particular, we show that the absence of H2Bub affects replication dynamics (enhanced fork progression and reduced origin firing), leading to γH2A accumulation and increased hydroxyurea sensitivity. Further genetic analysis indicates a role for H2Bub in transducing Rad53 phosphorylation. Concomitantly, we found that a change in replication dynamics is not due to a change in dNTP level, but is mediated by reduced Rad53 activation and destabilization of the RecQ helicase Sgs1 at the fork. Furthermore, we demonstrate that H2Bub facilitates the dissociation of the histone chaperone Asf1 from Rad53, and nucleosome reassembly behind the fork is compromised in cells lacking H2Bub. Taken together, these results indicate that the regulation of H2B ubiquitylation is a key event in the maintenance of genome stability, through coordination of intra-S checkpoint activation, chromatin assembly and replication fork progression. S.cerevisiae oligonucleotide microarrays were provided by Affymetrix (S.cerevisiae Tiling 1.0R, P/N 900645). BrdU and proteins ChIP-chip analyses were carried out as described (Fachinetti et al., M Cell, 2010).
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Project description:Structurally complex genomic regions, such as centromeres, are inherently difficult to duplicate. The mechanism that underlies centromere inheritance is not well understood, and one of the key questions relates to the reassembly of centromeric chromatin following DNA replication. Here we define the SNF2 ATPase ERCC6L2 as a key regulator of this process. ERCC6L2 accumulates at centromeres and promotes efficient deposition of core centromeric factors. Our genomic analyses show that ERCC6L2 deficiency erodes centromeric chromatin, leading to unrestrained replication of centromeric DNA. We also establish that, beyond centromeres, ERCC6L2 facilitates replication at genomic repeats and non-canonical DNA structures. Notably, ERCC6L2 interacts with the major DNA replication factor PCNA through an atypical peptide, presented here as a co-crystal structure. Finally, we examine ERCC6L2 activities at DNA breaks, and show that it acts to restrict end resection independently of the 53BP1-REV7-Shieldin complex. Our observations allow us to propose a mechanistic model of ERCC6L2 activity, which reconciles its seemingly distinct functions in DNA repair and DNA replication. Together, these findings provide a new molecular context for studies linking ERCC6L2 to human disease.
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Project description:The influence of mono-ubiquitylation of histone H2B (H2Bub) on transcription via nucleosome reassembly has been widely documented. Recently, it has also been shown that H2Bub promotes recovery from replication stress; however, the underling molecular mechanism remains unclear. Here, we show that H2B ubiquitylation coordinates activation of the intra-S replication checkpoint and chromatin re-assembly, in order to limit fork progression and DNA damage in the presence of replication stress. In particular, we show that the absence of H2Bub affects replication dynamics (enhanced fork progression and reduced origin firing), leading to γH2A accumulation and increased hydroxyurea sensitivity. Further genetic analysis indicates a role for H2Bub in transducing Rad53 phosphorylation. Concomitantly, we found that a change in replication dynamics is not due to a change in dNTP level, but is mediated by reduced Rad53 activation and destabilization of the RecQ helicase Sgs1 at the fork. Furthermore, we demonstrate that H2Bub facilitates the dissociation of the histone chaperone Asf1 from Rad53, and nucleosome reassembly behind the fork is compromised in cells lacking H2Bub. Taken together, these results indicate that the regulation of H2B ubiquitylation is a key event in the maintenance of genome stability, through coordination of intra-S checkpoint activation, chromatin assembly and replication fork progression.
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