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Replication-IDentifier links epigenetic and metabolic pathways to the replication stress response

Author

Listed:
  • Sophie C. Horst

    (Leiden University Medical Center)

  • Leonie Kollenstart

    (Leiden University Medical Center
    University of Copenhagen)

  • Amandine Batté

    (Leiden University Medical Center)

  • Sander Keizer

    (Leiden University Medical Center)

  • Kees Vreeken

    (Leiden University Medical Center)

  • Praveen Pandey

    (Umeå University)

  • Andrei Chabes

    (Umeå University)

  • Haico Attikum

    (Leiden University Medical Center)

Abstract

Perturbation of DNA replication, for instance by hydroxyurea-dependent dNTP exhaustion, often leads to stalling or collapse of replication forks. This triggers a replication stress response that stabilizes these forks, activates cell cycle checkpoints, and induces expression of DNA damage response genes. While several factors are known to act in this response, the full repertoire of proteins involved remains largely elusive. Here, we develop Replication-IDentifier (Repli-ID), which allows for genome-wide identification of regulators of DNA replication in Saccharomyces cerevisiae. During Repli-ID, the replicative polymerase epsilon (Pol ε) is tracked at a barcoded origin of replication by chromatin immunoprecipitation (ChIP) coupled to next-generation sequencing of the barcode in thousands of hydroxyurea-treated yeast mutants. Using this approach, 423 genes that promote Pol ε binding at replication forks were uncovered, including LGE1 and ROX1. Mechanistically, we show that Lge1 affects replication initiation and/or fork stability by promoting Bre1-dependent H2B mono-ubiquitylation. Rox1 affects replication fork progression by regulating S-phase entry and checkpoint activation, hinging on cellular ceramide levels via transcriptional repression of SUR2. Thus, Repli-ID provides a unique resource for the identification and further characterization of factors and pathways involved in the cellular response to DNA replication perturbation.

Suggested Citation

  • Sophie C. Horst & Leonie Kollenstart & Amandine Batté & Sander Keizer & Kees Vreeken & Praveen Pandey & Andrei Chabes & Haico Attikum, 2025. "Replication-IDentifier links epigenetic and metabolic pathways to the replication stress response," Nature Communications, Nature, vol. 16(1), pages 1-16, December.
  • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-56561-y
    DOI: 10.1038/s41467-025-56561-y
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    References listed on IDEAS

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    1. Massimo Lopes & Cecilia Cotta-Ramusino & Achille Pellicioli & Giordano Liberi & Paolo Plevani & Marco Muzi-Falconi & Carol S. Newlon & Marco Foiani, 2001. "The DNA replication checkpoint response stabilizes stalled replication forks," Nature, Nature, vol. 412(6846), pages 557-561, August.
    2. Laura D. Gallego & Maren Schneider & Chitvan Mittal & Anete Romanauska & Ricardo M. Gudino Carrillo & Tobias Schubert & B. Franklin Pugh & Alwin Köhler, 2020. "Phase separation directs ubiquitination of gene-body nucleosomes," Nature, Nature, vol. 579(7800), pages 592-597, March.
    3. Bertrand Theulot & Laurent Lacroix & Jean-Michel Arbona & Gael A. Millot & Etienne Jean & Corinne Cruaud & Jade Pellet & Florence Proux & Magali Hennion & Stefan Engelen & Arnaud Lemainque & Benjamin , 2022. "Genome-wide mapping of individual replication fork velocities using nanopore sequencing," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    4. Yuki Katou & Yutaka Kanoh & Masashige Bando & Hideki Noguchi & Hirokazu Tanaka & Toshihiko Ashikari & Katsunori Sugimoto & Katsuhiko Shirahige, 2003. "S-phase checkpoint proteins Tof1 and Mrc1 form a stable replication-pausing complex," Nature, Nature, vol. 424(6952), pages 1078-1083, August.
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