MDC1 counteracts replication fork reversal and mediates chemosensitivity in BRCA1/2-deficient tumors
MDC1 is a key protein in DNA damage signaling. When DNA double-strand breaks (DSBs) occur, MDC1 localizes to the sites of DNA damage to promote the recruitment of other factors, including the 53BP1-mediated DSB repair pathway. By studying mechanisms of poly (ADP-ribose) polymerase inhibitor (PARPi) resistance in BRCA2; p53-deficient mouse mammary tumors, we identified a thus far unknown role of MDC1 in replication fork biology. Our results show that MDC1 localizes at active replication forks during normal DNA replication and regulates replication fork progression. It suppresses spontaneous fork reversal and regulates fork nucleolytic processing thereby promoting sensitivity to PARPi and cisplatin. In this way, MDC1 loss improves DNA damage tolerance and causes chemoresistance in BRCA1/2-deficient cells. We demonstrate that limiting MRE11 activity abolishes the reduced fork speed while MRE11 inhibition/depletion overcomes PARPi resistance in these cells. Overall, our data provides new insights into the role of MDC1 in replication fork progression that mediates PARPi- and cisplatin-induced DNA damage, in addition to its role in DSB repair.
Authors
- Myriam Siffert
- Marieke van de Ven (ORCID: https://orcid.org/0000-0001-6779-9353)
- Ismar Klebic
- Diego Dibitetto (ORCID: https://orcid.org/0000-0002-9549-5258)
- Sven Rottenberg (ORCID: https://orcid.org/0000-0003-2044-9844)
- Massimo Lopes (ORCID: https://orcid.org/0000-0003-3847-8133)
- Martin Liptay (ORCID: https://orcid.org/0000-0001-8530-0800)
- Israel Salguero (ORCID: https://orcid.org/0000-0001-8756-659X)
- Jonas Schmid (ORCID: https://orcid.org/0000-0003-1791-1874)
- Ewa Gogola (ORCID: https://orcid.org/0000-0002-5733-770X)
- Renske de Korte‐Grimmerink
- Jos Jonkers (ORCID: https://orcid.org/0000-0002-9264-9792)
- Paola Francica (ORCID: https://orcid.org/0009-0005-4988-5940)
- Stephen P. Jackson (ORCID: https://orcid.org/0000-0001-9317-7937)
- Joana S. Barbosa
- Merve Mutlu (ORCID: https://orcid.org/0000-0003-3680-4476)
- Alexandra A. Duarte
- Hülya Dogan (ORCID: https://orcid.org/0000-0002-2698-6061)
Institutions
- University of Bern (CH)
- Bern University of Applied Sciences (CH)
- Mario Negri Institute for Pharmacological Research (IT)
- University of Zurich (CH)
- University of Cambridge (GB)
- Cancer Research UK (GB)
- The Gurdon Institute (GB)
- The Netherlands Cancer Institute (NL)
- Spanish National Cancer Research Centre (ES)
- Oncode Institute (NL)
- Cancer Genomics Centre (NL)
- Centro de Investigación del Cáncer (ES)
Publication Details
- Journal
- Oncogene
- Published
- 2025-12-17
- DOI
- https://doi.org/10.1038/s41388-025-03659-8
- Primary Topic
- DNA Repair Mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- National Science Foundation
- Boehringer Ingelheim Fonds
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
- Associazione Italiana per la Ricerca sul Cancro
- Horizon 2020 Framework Programme