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3D genome organization, transcription and aberrant DNA replication contribute to genome instability at fragile sites

ABSTRACT: Common fragile sites (CFSs) are regions susceptible to replication stress and are hotspots for chromosomal instability in cancer. Several features characterizing CFSs have been associated with their instability, however, these features are prevalent across the genome and do not account for all known CFSs. Here we explored the transcriptional profile and DNA replication timing under mild replication stress in the context of the 3D genome organization. We report the analysis of nascent RNA-seq for high-throughput profiling of gene expression in human fibroblasts (BJ-hTERT), grown with or without aphidicolin, a DNA polymerase inhibitor used to induce CFS expression. We find that aphidicolin treatment does not affect the transcriptional program. However, large expressed genes are susceptible to replication timing delay under stress. We further study the mechanism leading to recurrent chromosomal instability at CFSs and find that the 3D genome organization underlies fragility at large expressed genes. We report a fragility signature at the core of CFSs comprised of a large expressed gene spanning over a TAD-boundary with delayed DNA replication. The fragility signature allows for mapping of the core fragile site and the identification of novel fragile sites in BJ cells.

ORGANISM(S): Homo sapiens

PROVIDER: GSE150354 | GEO | 2020/06/08

REPOSITORIES: GEO

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3D genome organization, transcription and aberrant DNA replication contribute to genome instability at fragile sites

Project description:Common fragile sites (CFSs) are regions susceptible to replication stress and are hotspots for chromosomal instability in cancer. Several features characterizing CFSs have been associated with their instability, however, these features are prevalent across the genome and do not account for all known CFSs. Here we explored the DNA replication timing (RT) and transcriptional profile under mild replication stress in the context of the 3D genome organization. We report the analysis of DNA replication timing profiling of human fibroblasts (BJ-hTERT), grown with or without aphidicolin, a DNA polymerase inhibitor used to induce CFS expression. We find that aphidicolin treatment affects the RT of a small portion of the genome. However, CFSs are enriched for delayed RT regions under stress. We further study the mechanism leading to recurrent chromosomal instability at CFSs and find that the 3D genome organization underlies fragility at RT delayed large expressed genes. We report a fragility signature at the core of CFSs comprised of delayed replication of large expressed gene spanning over a TAD-boundary. The fragility signature allows for mapping of the core fragile site and the identification of novel fragile sites in BJ cells.

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Genome-wide replication dynamics quantification reveals stress-induced delayed/under-replication as a hallmark of CFSs

Project description:We report Repli-Seq analysis of the replication program in human lymphoblasts grown in the absence or in the presence of aphidicolin, an inhibitor of replicative DNA polymerases used in vitro to destabilize CFSs. We identified regions displaying specific replication delay upon aphidicolin treatment, resulting in under-replication. We then further study the mechanisms leading to such specific delayed/under-replication within CFSs and show that transcription-dependent segregation of initiation events out of the gene body generates long-traveling forks in large transcribed domains, which elicits the replication timing delay responsible for CFS instability upon replication stress.

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Replication timing data for six human cell lines under aphidicolin treatment (t0) and after release (N+1)

Project description:DNA replication is very well orchestrated in mammalian cells due to a tight regulation of the temporal order of replication origin activation, known as the replication timing program. The replication timing of a given replication domain is very robust and well conserved in each cell type. Upon low replication stress, the slowing of replication forks induces delayed replication of some fragile regions leading to DNA damage and genetic instability. Except for these fragile regions, the direct impact of low replication stress on the replication timing in different cellular backgrounds has not been explored in detail. Here we analysed DNA replication timing across the whole genome in a panel of human cell lines in the presence of low replication stress. We demonstrate that low replication stress induced by aphidicolin has a stronger impact on the replication timing of cancer cells than non-tumour cells. Strikingly, we unveiled an enrichment of specific replication domains undergoing a switch from late to early replication in some cancer cells. We found that advances in replication timing correlate with heterochromatin regions poorly sensitive to DNA damage signalling while being subject to an increase of chromatin accessibility in response to aphidicolin. Finally, our data indicate that, following release from replication stress conditions, replication timing advances can be inherited by the next cellular generation, suggesting a new mechanism by which some cancer cells would adapt to cellular or environmental stress.

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Bru-seq nascent RNA sequencing of human and mouse cells: correlation to replication timing and genome instability

Project description:Bru-seq nascent RNA sequencing (PubMed ID 23973811) was performed on two primary human fibroblast cell lines, mouse embryonic stem cells, and GM12878 human lymphoblastoid cells. Read data, which include both exon and intron signals, were used to identify transcription unit spans genome-wide, where a transcription unit is roughly correspondent to the longest expressed isoform of a gene. However, because algorithms were not constrained by annotated genes, transcription units need not and often do not correspond precisely to gene boundaries and include extragenic transcription. Transcription units were then compared to separate data sets that comprised induced copy number variants, common fragile sites, and Repli-seq replication timing. The objective was to discover the relationships between transcription unit span and size, local genomic instability, and replication timing. This GEO sample series provides the span and intensity of transcription units called genome-wide in the various samples. Correlations to genome stability and replication timing are provided in the associated manuscript. In addition, one human fibroblast line and the mouse embryonic stem cells had paired samples treated and untreated with low dose aphidicolin. Gene RPKM signal intensities are provided for these samples, although comparing these was not the principal objective of the study. Bru-seq single-read nascent RNA sequencing on human 090 fibroblasts +/- aphidicolin treatment, human UMHF1 fibroblasts (3 replicates), human GM12878 lymphoblastoid cells, and mouse embryonic stem cells+/- aphidicolin treatment.

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Project description:Genome integrity requires replication to be completed before chromosome segregation. This coordination essentially relies on replication-dependent activation of a dedicated checkpoint that inhibits CDK1, delaying mitotic onset. Under-replication of Common Fragile Sites (CFSs), however, escapes surveillance, which generates mitotic chromosome breaks. Using human cells, we asked whether this leakage results from insufficient CDK1 inhibition under modest stresses used to destabilize CFSs. We found that tight CDK1 inhibition does suppress CFS instability in so-stressed cells. Molecular combing and Repli-Seq analyses consistently showed a burst of replication initiations in mid S-phase across large origin-poor domains shaped by transcription, including CFSs. CFS rescue and extra-initiations strikingly require availability of essential pre-Replication Complex (pre-RC) proteins during the S-phase, showing that CDK1 inhibition promotes targeted and mistimed pre-RC reloading. In addition to delay mitotic onset, tight checkpoint activation therefore advances replication completion of origin-poor domains at risk of under-replication, two complementary roles preserving genome stability.

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TDP1 phosphorylation at S61 promotes Top1cc repair via the MUS81-dependent pathway during mitosis

Project description:Topoisomerase 1 (Top1) removes supercoils from DNA during replication and transcription, is critical for mitotic progression to the G1 phase, and ensures DNA topology. Tyrosyl-DNA phosphodiesterase 1 (TDP1) mediates the removal of trapped Top1-DNA covalent complexes (Top1ccs). Here, we identify CDK1-dependent phosphorylation of TDP1 at S61 residue during mitosis. TDP1 defective for S61 phosphorylation (TDP1S61A) is trapped on the mitotic chromosomes, triggering DNA damage and mitotic defects. Moreover, we show that Top1cc repair in mitosis occurs via MUS81-dependent mitotic DNA repair mechanism. Replication stress (RS) induced by Camptothecin (CPT) or Aphidicolin (APH) leads to TDP1S61A enrichment at common fragile sites (CFSs), which over-stimulates MUS81-dependent chromatid breaks, anaphase bridges, and micronuclei, ultimately culminating in 53BP1 nuclear bodies in the G1-phase. Our findings provide a new insight into the cell cycle-dependent regulation of TDP1 dynamics forthe repair of trapped Top1ccs during mitosis that prevents genomic instability following RS.

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Replication timing for the replication fountains

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