MDC1 counteracts replication fork reversal and mediates chemosensitivity in BRCA1/2-deficient tumors.
Publisher DOI
PubMed ID
41408464
Abstract
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.
Date Issued
2026-02
Publication Type
Article
Language(s)
en
Author(s)
Institute of Animal Pathology, Laboratory Cancer Therapy Escape I | |
Gogola, Ewa | |
Duarte, Alexandra A | |
Schmid, Jonas A | |
Institute of Animal Pathology, Laboratory Cancer Therapy Escape I | |
Salguero, Israel | |
van de Ven, Marieke | |
de Korte-Grimmerink, Renske | |
Jackson, Stephen P | |
Jonkers, Jos | |
Lopes, Massimo | |
Institute of Animal Pathology, Laboratory Cancer Therapy Escape I | |
Additional Credits
Institute of Animal Pathology, Laboratory Cancer Therapy Escape I
Journal
Oncogene
Publisher
Springer Nature [academic journals on nature.com]
ISSN
1476-5594
0950-9232
Access(Rights)
open.access