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DNA double-strand break end resection factors and WRN facilitate mitotic DNA synthesis in human cells

Author

Listed:
  • Szymon A. Barwacz

    (University of Copenhagen)

  • Katrine Lundgaard

    (University of Copenhagen)

  • Wei Wu

    (University of Copenhagen
    Zhejiang University)

  • Philipp H. Richter

    (University of Copenhagen)

  • Liqun Ren

    (University of Copenhagen
    Chengde Medical University)

  • Rahul Bhowmick

    (University of Copenhagen
    Vanderbilt University School of Medicine)

  • Marisa M. Gonçalves Dinis

    (University of Copenhagen)

  • Masato T. Kanemaki

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

  • Ying Liu

    (University of Copenhagen)

Abstract

Mitotic DNA synthesis (MiDAS) serves to complete the replication of genomic loci that are not fully replicated in S phase in response to replication stress. Previous studies suggest that MiDAS might proceed via break-induced DNA replication, a sub-pathway of homologous recombination repair activated at broken or collapsed replication forks. We set out to define whether DNA double strand break end-resection factors play a role in MiDAS. Here, we show that several core end-resection factors, including MRE11, CtIP and BRCA1 are essential for MiDAS. In addition, while loss of WRN or DNA2 impairs MiDAS, there is no requirement for other known end-resection factors such as EXO1 and BLM. Moreover, both the exonuclease and the helicase activities of WRN contribute to MiDAS. Because oncogene-induced replication stress is common in cancers, targeting of WRN or other factors required for MiDAS could facilitate the development of targeted cancer therapies.

Suggested Citation

  • Szymon A. Barwacz & Katrine Lundgaard & Wei Wu & Philipp H. Richter & Liqun Ren & Rahul Bhowmick & Marisa M. Gonçalves Dinis & Masato T. Kanemaki & Ying Liu, 2025. "DNA double-strand break end resection factors and WRN facilitate mitotic DNA synthesis in human cells," Nature Communications, Nature, vol. 16(1), pages 1-20, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-63292-7
    DOI: 10.1038/s41467-025-63292-7
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