DNA double-strand break end resection factors and WRN facilitate mitotic DNA synthesis in human cells
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.
Authors
- Masato T. Kanemaki (ORCID: https://orcid.org/0000-0002-7657-1649)
- Marisa M. Gonçalves Dinis (ORCID: https://orcid.org/0000-0002-4058-6443)
- Katrine Lundgaard (ORCID: https://orcid.org/0000-0003-0722-7147)
- Rahul Bhowmick (ORCID: https://orcid.org/0000-0002-5412-1209)
- Ying Liu (ORCID: https://orcid.org/0000-0003-3703-2498)
- Petra Richter (ORCID: https://orcid.org/0000-0003-4848-6567)
- Szymon A. Barwacz (ORCID: https://orcid.org/0000-0001-7116-6241)
- Liqun Ren (ORCID: https://orcid.org/0000-0002-1132-8613)
- Wei Wu (ORCID: https://orcid.org/0000-0003-3929-2090)
Institutions
- National Institute of Genetics (JP)
- University of Copenhagen (DK)
- Chengde Medical University (CN)
- The Graduate University for Advanced Studies, SOKENDAI (JP)
- Vanderbilt University (US)
- Research Organization of Information and Systems (JP)
- The University of Tokyo (JP)
- Zhejiang University (CN)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-08-25
- DOI
- https://doi.org/10.1038/s41467-025-63292-7
- Citations
- 4
- Primary Topic
- DNA Repair Mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 3.22
Funders
- Dagmar Marshalls Fond
- European Commission
- National Research Foundation
- Danmarks Grundforskningsfond
- National Natural Science Foundation of China
- Horizon 2020 Framework Programme
- H2020 Marie Skłodowska-Curie Actions