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

  • Nat Commun. 2025 Aug 25;16(1):7901. doi: 10.1038/s41467-025-63292-7.
Szymon A Barwacz  1 ,  Katrine Lundgaard  1 ,  Wei Wu  1  2 ,  Philipp H Richter  1 ,  Liqun Ren  1  3 ,  Rahul Bhowmick  1  4 ,  Marisa M Gonçalves Dinis  1 ,  Masato T Kanemaki  5  6 ,  Ying Liu  7
Affiliations
  • 1. Center for Chromosome Stability, Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark.
  • 2. MOA Key Laboratory of Animal Virology, Center for Veterinary Sciences, Zhejiang University, Hangzhou, Zhejiang, China.
  • 3. Basic Medical Research Institute, Chengde Medical University, Chengde, China.
  • 4. Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN, USA.
  • 5. Department of Chromosome Science, National Institute of Genetics, Research Organization of Information and Systems (ROIS); Graduate Institute for Advanced Studies, SOKENDAI, Shizuoka, Japan.
  • 6. Department of Biological Science, Graduate School of Science, The University of Tokyo, Bunkyo-ku, Tokyo, Japan.
  • 7. Center for Chromosome Stability, Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark. [email protected].
PMID: 40854910 DOI: 10.1038/s41467-025-63292-7
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.

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