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Unscheduled DNA replication in G1 causes genome instability and damage signatures indicative of replication collisions

Author

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  • Karl-Uwe Reusswig

    (Max Planck Institute of Biochemistry
    Blavatnik Institute, Harvard Medical School
    Dana-Farber Cancer Institute)

  • Julia Bittmann

    (Max Planck Institute of Biochemistry)

  • Martina Peritore

    (Max Planck Institute of Biochemistry
    Institute of Aerospace Medicine, German Aerospace Center (DLR))

  • Mathilde Courtes

    (Université de Montpellier – Centre National de la Recherche Scientifique)

  • Benjamin Pardo

    (Université de Montpellier – Centre National de la Recherche Scientifique)

  • Michael Wierer

    (Max Planck Institute of Biochemistry
    University of Copenhagen)

  • Matthias Mann

    (Max Planck Institute of Biochemistry)

  • Boris Pfander

    (Max Planck Institute of Biochemistry
    Institute of Aerospace Medicine, German Aerospace Center (DLR)
    CECAD Research Center, University of Cologne)

Abstract

DNA replicates once per cell cycle. Interfering with the regulation of DNA replication initiation generates genome instability through over-replication and has been linked to early stages of cancer development. Here, we engineer genetic systems in budding yeast to induce unscheduled replication in a G1-like cell cycle state. Unscheduled G1 replication initiates at canonical S-phase origins. We quantifiy the composition of replisomes in G1- and S-phase and identified firing factors, polymerase α, and histone supply as factors that limit replication outside S-phase. G1 replication per se does not trigger cellular checkpoints. Subsequent replication during S-phase, however, results in over-replication and leads to chromosome breaks and chromosome-wide, strand-biased occurrence of RPA-bound single-stranded DNA, indicating head-to-tail replication collisions as a key mechanism generating genome instability upon G1 replication. Low-level, sporadic induction of G1 replication induces an identical response, indicating findings from synthetic systems are applicable to naturally occurring scenarios of unscheduled replication initiation.

Suggested Citation

  • Karl-Uwe Reusswig & Julia Bittmann & Martina Peritore & Mathilde Courtes & Benjamin Pardo & Michael Wierer & Matthias Mann & Boris Pfander, 2022. "Unscheduled DNA replication in G1 causes genome instability and damage signatures indicative of replication collisions," Nature Communications, Nature, vol. 13(1), pages 1-20, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-34379-2
    DOI: 10.1038/s41467-022-34379-2
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    2. Arianna Penzo & Marion Dubarry & Clémentine Brocas & Myriam Zheng & Raphaël M. Mangione & Mathieu Rougemaille & Coralie Goncalves & Ophélie Lautier & Domenico Libri & Marie-Noëlle Simon & Vincent Géli, 2023. "A R-loop sensing pathway mediates the relocation of transcribed genes to nuclear pore complexes," Nature Communications, Nature, vol. 14(1), pages 1-15, December.

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