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DNA replication timing reveals genome-wide features of transcription and fragility

Author

Listed:
  • Francisco Berkemeier

    (University of Cambridge
    University of Cambridge)

  • Peter R. Cook

    (University of Oxford)

  • Michael A. Boemo

    (University of Cambridge
    University of Cambridge)

Abstract

DNA replication in humans requires precise regulation to ensure accurate genome duplication and maintain genome integrity. A key indicator of this regulation is replication timing, which reflects the interplay between origin firing and fork dynamics. We present a high-resolution (1-kilobase) mathematical model that infers firing rate distributions from Repli-seq timing data across multiple cell lines, enabling a genome-wide comparison between predicted and observed replication. Notably, regions where the model and data diverge often overlap fragile sites and long genes, highlighting the influence of genomic architecture on replication dynamics. Conversely, regions of strong concordance are associated with open chromatin and active promoters, where elevated firing rates facilitate timely fork progression and reduce replication stress. In this work, we provide a valuable framework for exploring the structural interplay between replication timing, transcription, and chromatin organisation, offering insights into the mechanisms underlying replication stress and its implications for genome stability and disease.

Suggested Citation

  • Francisco Berkemeier & Peter R. Cook & Michael A. Boemo, 2025. "DNA replication timing reveals genome-wide features of transcription and fragility," Nature Communications, Nature, vol. 16(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-59991-w
    DOI: 10.1038/s41467-025-59991-w
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    References listed on IDEAS

    as
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    4. Dashiell J. Massey & Amnon Koren, 2022. "High-throughput analysis of single human cells reveals the complex nature of DNA replication timing control," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    5. Lorenzo Corazzi & Vivien S. Ionasz & Sergej Andrejev & Li-Chin Wang & Athanasios Vouzas & Marco Giaisi & Giulia Di Muzio & Boyu Ding & Anna J. M. Marx & Jonas Henkenjohann & Michael M. Allers & David , 2024. "Linear interaction between replication and transcription shapes DNA break dynamics at recurrent DNA break Clusters," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    6. Olivier Brison & Sami El-Hilali & Dana Azar & Stéphane Koundrioukoff & Mélanie Schmidt & Viola Nähse & Yan Jaszczyszyn & Anne-Marie Lachages & Bernard Dutrillaux & Claude Thermes & Michelle Debatisse , 2019. "Transcription-mediated organization of the replication initiation program across large genes sets common fragile sites genome-wide," Nature Communications, Nature, vol. 10(1), pages 1-12, December.
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