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MDC1 counteracts replication fork reversal and mediates chemosensitivity in BRCA1/2-deficient tumors

Hülya Dogan1, Martin Liptay1, Joana S Barbosa1

  • 1Institute of Animal Pathology, Vetsuisse Faculty, University of Bern, Bern, 3012, Switzerland.

Oncogene
|December 17, 2025
PubMed

Insights

Mediator of DNA damage checkpoint 1 (MDC1) protein is crucial for DNA repair and replication fork stability. Loss of MDC1 promotes chemoresistance in BRCA1/2-deficient cells by altering DNA damage tolerance.

Area of Science:

  • Molecular Biology
  • Genetics
  • Cancer Research

Background:

  • Mediator of DNA damage checkpoint 1 (MDC1) is a key protein in DNA damage signaling, particularly in response to DNA double-strand breaks (DSBs).
  • MDC1 facilitates the recruitment of repair factors, such as those involved in the 53BP1-mediated DSB repair pathway.
  • Understanding mechanisms of poly (ADP-ribose) polymerase inhibitor (PARPi) resistance is critical for cancer therapy.

Purpose of the Study:

  • To investigate the role of MDC1 in replication fork biology and its contribution to PARPi resistance in BRCA2-deficient, p53-deficient mouse mammary tumors.
  • To elucidate how MDC1 influences DNA damage tolerance and sensitivity to chemotherapeutic agents like PARPi and cisplatin.

Main Methods:

  • Analysis of BRCA2; p53-deficient mouse mammary tumors to study PARPi resistance mechanisms.
  • Investigation of MDC1 localization at active replication forks during normal DNA replication.
  • Assessment of MDC1's role in regulating replication fork progression, fork reversal, and nucleolytic processing.
  • Evaluation of MRE11 activity's impact on fork speed and PARPi resistance.

Main Results:

  • MDC1 localizes to active replication forks and regulates their progression during normal DNA replication.
  • MDC1 suppresses spontaneous replication fork reversal and controls fork nucleolytic processing, promoting sensitivity to PARPi and cisplatin.
  • Loss of MDC1 enhances DNA damage tolerance and confers chemoresistance in BRCA1/2-deficient cells.
  • Limiting MRE11 activity reduces fork speed and overcomes PARPi resistance in MDC1-deficient cells.

Conclusions:

  • MDC1 plays a significant role in replication fork progression, influencing sensitivity to DNA-damaging agents.
  • MDC1's function at replication forks is distinct from its established role in DSB repair.
  • Targeting MRE11 activity presents a potential strategy to overcome PARPi resistance in cancers with altered MDC1 function.

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