ArticleGenome biology2022
Replication stress generates distinctive landscapes of DNA copy number alterations and chromosome scale losses.
Article in Genome biology, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 34 papers.
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Who cites it
34 citing papers in PubMed, 41 citations in OpenAlex.
- Single-cell mapping of chromosome breaks identifies multiple fragile site classes with distinct DNA replication timing landscapes.Nature communications · 2026Article
- Article
- Telomere-driven replicative crisis is driven by large-scale changes in genomic architecture.Genome research · 2026Article
- Apoptosis-driven chromosomal rearrangements in cancer: CAD cleavage, nuclear architecture, and microhomology-mediated end joining.Oncogenesis · 2026Review
- Replication origin firing capacity indicates ATR inhibitor sensitivity.Nature communications · 2026Article
- Recurrent DNA break clusters drive replication-stress-induced copy number variants and genome diversification.Nature communications · 2026Article
- Mitotic BLM functions are required to maintain genomic stability.Nucleic acids research · 2026Article
- Investigating the Consequences of Aneuploidy in Cancer and Normal Tissue.Advances in experimental medicine and biology · 2026Review
- Immunofluorescent microscopy to quantify and characterize chromosomal instability (CIN).Methods in cell biology · 2026Article
- Identification of DNA Replication Stress-Related Genes as Prognostic Biomarkers for Bladder Cancer.Combinatorial chemistry & high throughput screening · 2026Article
- scRepli-RamDA-seq: a multi-omics technology enabling the analysis of gene expression dynamics during S-phase.Nature communications · 2025Article
- The Puzzle of Genetic Stability and Chromosomal Copy Number Alterations for the Therapy of Ewing Sarcoma.Cancers · 2025Review
- ChromoPattern: characterizing chromosomal rearrangement patterns of copy number alteration in heterogeneous tumor cell populations at single-cell resolution.Briefings in bioinformatics · 2025Article
- Unravelling single-cell DNA replication timing dynamics using machine learning reveals heterogeneity in cancer progression.Nature communications · 2025Article
- 53BP1-the 'Pandora's box' of genome integrity.DNA repair · 2024Review
- Inferring replication timing and proliferation dynamics from single-cell DNA sequencing data.Nature communications · 2024Article
- Review
- Patterns of Aneuploidy and Signaling Consequences in Cancer.Cancer research · 2024Review
- Transient ZnProceedings of the National Academy of Sciences of the United States of America · 2024Article
- Experimental evolution of cancer chromosomal changes.Nature genetics · 2024Article
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Authors and funding
12 authors at 3 institutions in 2 countries.
Funding
Abstract
backgroundA major driver of cancer chromosomal instability is replication stress, the slowing or stalling of DNA replication. How replication stress and genomic instability are connected is not known. Aphidicolin-induced replication stress induces breakages at common fragile sites, but the exact causes of fragility are debated, and acute genomic consequences of replication stress are not fully explored.
resultsWe characterize DNA copy number alterations (CNAs) in single, diploid non-transformed cells, caused by one cell cycle in the presence of either aphidicolin or hydroxyurea. Multiple types of CNAs are generated, associated with different genomic regions and features, and observed copy number landscapes are distinct between aphidicolin and hydroxyurea-induced replication stress. Coupling cell type-specific analysis of CNAs to gene expression and single-cell replication timing analyses pinpointed the causative large genes of the most recurrent chromosome-scale CNAs in aphidicolin. These are clustered on chromosome 7 in RPE1 epithelial cells but chromosome 1 in BJ fibroblasts. Chromosome arm level CNAs also generate acentric lagging chromatin and micronuclei containing these chromosomes.
conclusionsChromosomal instability driven by replication stress occurs via focal CNAs and chromosome arm scale changes, with the latter confined to a very small subset of chromosome regions, potentially heavily skewing cancer genome evolution. Different inducers of replication stress lead to distinctive CNA landscapes providing the opportunity to derive copy number signatures of specific replication stress mechanisms. Single-cell CNA analysis thus reveals the impact of replication stress on the genome, providing insights into the molecular mechanisms which fuel chromosomal instability in cancer.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.