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Mitotic DNA synthesis in response to replication stress requires the sequential action of DNA polymerases zeta and delta in human cells

Author

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  • Wei Wu

    (University of Copenhagen
    First Affiliated Hospital of Zhejiang University)

  • Szymon A. Barwacz

    (University of Copenhagen)

  • Rahul Bhowmick

    (University of Copenhagen
    Vanderbilt University School of Medicine)

  • Katrine Lundgaard

    (University of Copenhagen)

  • Marisa M. Gonçalves Dinis

    (University of Copenhagen)

  • Malgorzata Clausen

    (University of Copenhagen)

  • Masato T. Kanemaki

    (National Institute of Genetics, Research Organization of Information and Systems (ROIS)
    The Graduate University for Advanced Studies (SOKENDAI))

  • Ying Liu

    (University of Copenhagen)

Abstract

Oncogene activation creates DNA replication stress (RS) in cancer cells, which can generate under-replicated DNA regions (UDRs) that persist until cells enter mitosis. UDRs also have the potential to generate DNA bridges in anaphase cells or micronuclei in the daughter cells, which could promote genomic instability. To suppress such damaging changes to the genome, human cells have developed a strategy to conduct ‘unscheduled’ DNA synthesis in mitosis (termed MiDAS) that serves to rescue under-replicated loci. Previous studies have shown that MiDAS proceeds via a POLD3-dependent pathway that shows some features of break-induced replication. Here, we define how human cells utilize both DNA gap filling (REV1 and Pol ζ) and replicative (Pol δ) DNA polymerases to complete genome duplication following a perturbed S-phase. We present evidence for the existence of a polymerase-switch during MiDAS that is required for new DNA synthesis at UDRs. Moreover, we reveal that, upon oncogene activation, cancer cell survival is significantly compromised when REV1 is depleted, suggesting that REV1 inhibition might be a feasible approach for the treatment of some human cancers.

Suggested Citation

  • Wei Wu & Szymon A. Barwacz & Rahul Bhowmick & Katrine Lundgaard & Marisa M. Gonçalves Dinis & Malgorzata Clausen & Masato T. Kanemaki & Ying Liu, 2023. "Mitotic DNA synthesis in response to replication stress requires the sequential action of DNA polymerases zeta and delta in human cells," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-35992-5
    DOI: 10.1038/s41467-023-35992-5
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    1. Daniela Muoio & Natalie Laspata & Rachel L. Dannenberg & Caroline Curry & Simone Darkoa-Larbi & Mark Hedglin & Shikhar Uttam & Elise Fouquerel, 2024. "PARP2 promotes Break Induced Replication-mediated telomere fragility in response to replication stress," Nature Communications, Nature, vol. 15(1), pages 1-18, December.

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