MDC1 counteracts restrained replication fork restart and its loss causes chemoresistance in BRCA1/2-deficient mammary tumors

MDC1 is a key protein in DNA damage signaling. When DNA double-strand breaks (DSBs) occur, MDC1 localizes to sites of 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) resistanc...

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Hauptverfasser: Liptay, Martin, Barbosa, Joana S., Gogola, Ewa, Duarte, Alexandra A., Dibitetto, Diego, Schmid, Jonas A., Klebic, Ismar, Mutlu, Merve, Siffert, Myriam, Francica, Paola, Salguero, Israel, van de Ven, Marieke, Korte-Grimmerink, Renske de, Jackson, Stephen P., Jonkers, Jos, Lopes, Massimo, Rottenberg, Sven
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Sprache:Englisch
Veröffentlicht: Cold Spring Harbor Laboratory 19.08.2022
Ausgabe:1.1
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Molecular Biology
ISSN:2692-8205
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Abstract MDC1 is a key protein in DNA damage signaling. When DNA double-strand breaks (DSBs) occur, MDC1 localizes to sites of 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. MDC1 localizes at active replication forks during normal fork replication and its loss reduces fork speed. We show that MDC1 contributes to the restart of replication forks and thereby promotes sensitivity to PARPi and cisplatin. Loss of MDC1 causes MRE11-mediated resection, resulting in delayed fork restart. This improves DNA damage tolerance and causes chemoresistance in BRCA1/2-deficient cells. Hence, our results show a role for MDC1 in replication fork progression that mediates PARPi- and cisplatin-induced DNA damage, in addition to its role in DSB repair.
AbstractList MDC1 is a key protein in DNA damage signaling. When DNA double-strand breaks (DSBs) occur, MDC1 localizes to sites of 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. MDC1 localizes at active replication forks during normal fork replication and its loss reduces fork speed. We show that MDC1 contributes to the restart of replication forks and thereby promotes sensitivity to PARPi and cisplatin. Loss of MDC1 causes MRE11-mediated resection, resulting in delayed fork restart. This improves DNA damage tolerance and causes chemoresistance in BRCA1/2-deficient cells. Hence, our results show a role for MDC1 in replication fork progression that mediates PARPi- and cisplatin-induced DNA damage, in addition to its role in DSB repair.
Author Schmid, Jonas A.
Barbosa, Joana S.
Rottenberg, Sven
Gogola, Ewa
Dibitetto, Diego
Duarte, Alexandra A.
Korte-Grimmerink, Renske de
Liptay, Martin
Klebic, Ismar
Jackson, Stephen P.
Siffert, Myriam
Salguero, Israel
Jonkers, Jos
Lopes, Massimo
Francica, Paola
Mutlu, Merve
van de Ven, Marieke
Author_xml – sequence: 1
  givenname: Martin
  orcidid: 0000-0001-8530-0800
  surname: Liptay
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  organization: Institute of Animal Pathology, Vetsuisse Faculty, University of Bern
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  givenname: Joana S.
  surname: Barbosa
  fullname: Barbosa, Joana S.
  organization: Institute of Animal Pathology, Vetsuisse Faculty, University of Bern
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  givenname: Ewa
  orcidid: 0000-0002-5733-770X
  surname: Gogola
  fullname: Gogola, Ewa
  organization: Division of Molecular Pathology, The Netherlands Cancer Institute
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  givenname: Alexandra A.
  surname: Duarte
  fullname: Duarte, Alexandra A.
  organization: Division of Molecular Pathology, The Netherlands Cancer Institute
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  givenname: Diego
  surname: Dibitetto
  fullname: Dibitetto, Diego
  organization: Institute of Animal Pathology, Vetsuisse Faculty, University of Bern
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  surname: Schmid
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  organization: Institute of Molecular Cancer Research, University of Zurich
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  surname: Klebic
  fullname: Klebic, Ismar
  organization: Institute of Animal Pathology, Vetsuisse Faculty, University of Bern
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  givenname: Merve
  surname: Mutlu
  fullname: Mutlu, Merve
  organization: Institute of Animal Pathology, Vetsuisse Faculty, University of Bern
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  givenname: Myriam
  surname: Siffert
  fullname: Siffert, Myriam
  organization: Institute of Animal Pathology, Vetsuisse Faculty, University of Bern
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  surname: Francica
  fullname: Francica, Paola
  organization: Institute of Animal Pathology, Vetsuisse Faculty, University of Bern
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  givenname: Israel
  orcidid: 0000-0001-8756-659X
  surname: Salguero
  fullname: Salguero, Israel
  organization: Wellcome/Cancer Research UK Gurdon Institute, University of Cambridge
– sequence: 12
  givenname: Marieke
  surname: van de Ven
  fullname: van de Ven, Marieke
  organization: Mouse Clinic for Cancer and Aging Research (MCCA), Preclinical Intervention Unit, the Netherlands Cancer Institute
– sequence: 13
  givenname: Renske de
  surname: Korte-Grimmerink
  fullname: Korte-Grimmerink, Renske de
  organization: Mouse Clinic for Cancer and Aging Research (MCCA), Preclinical Intervention Unit, the Netherlands Cancer Institute
– sequence: 14
  givenname: Stephen P.
  surname: Jackson
  fullname: Jackson, Stephen P.
  organization: Wellcome/Cancer Research UK Gurdon Institute, University of Cambridge
– sequence: 15
  givenname: Jos
  surname: Jonkers
  fullname: Jonkers, Jos
  organization: Oncode Institute, The Netherlands Cancer Institute
– sequence: 16
  givenname: Massimo
  surname: Lopes
  fullname: Lopes, Massimo
  organization: Institute of Molecular Cancer Research, University of Zurich
– sequence: 17
  givenname: Sven
  orcidid: 0000-0003-2044-9844
  surname: Rottenberg
  fullname: Rottenberg, Sven
  email: sven.rottenberg@vetsuisse.unibe.ch
  organization: Bern Center for Precision Medicine, University of Bern
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Copyright 2022, Posted by Cold Spring Harbor Laboratory
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Notes Competing Interest Statement: The authors have declared no competing interest.
ORCID 0000-0003-2044-9844
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Snippet MDC1 is a key protein in DNA damage signaling. When DNA double-strand breaks (DSBs) occur, MDC1 localizes to sites of damage to promote the recruitment of...
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SubjectTerms Molecular Biology
Title MDC1 counteracts restrained replication fork restart and its loss causes chemoresistance in BRCA1/2-deficient mammary tumors
URI https://www.biorxiv.org/content/10.1101/2022.08.18.504391
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