Schoonen, Pepijn M; Talens, Francien; Stok, Colin; Gogola, Ewa; Heijink, Anne Margriet; Bouwman, Peter; Foijer, Floris; Tarsounas, Madalena; Blatter, Sohvi Tuulikki; Jonkers, Jos; Rottenberg, Sven; van Vugt, Marcel A T M (2017). Progression through mitosis promotes PARP inhibitor-induced cytotoxicity in homologous recombination-deficient cancer cells. Nature communications, 8(15981), p. 15981. Nature Publishing Group 10.1038/ncomms15981
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Mutations in homologous recombination (HR) genes BRCA1 and BRCA2 predispose to tumorigenesis. HR-deficient cancers are hypersensitive to Poly (ADP ribose)-polymerase (PARP) inhibitors, but can acquire resistance and relapse. Mechanistic understanding how PARP inhibition induces cytotoxicity in HR-deficient cancer cells is incomplete. Here we find PARP inhibition to compromise replication fork stability in HR-deficient cancer cells, leading to mitotic DNA damage and consequent chromatin bridges and lagging chromosomes in anaphase, frequently leading to cytokinesis failure, multinucleation and cell death. PARP-inhibitor-induced multinucleated cells fail clonogenic outgrowth, and high percentages of multinucleated cells are found in vivo in remnants of PARP inhibitor-treated Brca2;p53and Brca1;p53mammary mouse tumours, suggesting that mitotic progression promotes PARP-inhibitor-induced cell death. Indeed, enforced mitotic bypass through EMI1 depletion abrogates PARP-inhibitor-induced cytotoxicity. These findings provide insight into the cytotoxic effects of PARP inhibition, and point at combination therapies to potentiate PARP inhibitor treatment of HR-deficient tumours.
Item Type: |
Journal Article (Original Article) |
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Division/Institute: |
05 Veterinary Medicine > Research Foci > Host-Pathogen Interaction 05 Veterinary Medicine > Department of Infectious Diseases and Pathobiology (DIP) > Institute of Animal Pathology 05 Veterinary Medicine > Department of Infectious Diseases and Pathobiology (DIP) |
UniBE Contributor: |
Blatter, Sohvi Tuulikki, Rottenberg, Sven |
Subjects: |
500 Science > 570 Life sciences; biology 600 Technology > 610 Medicine & health 600 Technology > 630 Agriculture |
ISSN: |
2041-1723 |
Publisher: |
Nature Publishing Group |
Language: |
English |
Submitter: |
Pamela Schumacher |
Date Deposited: |
08 May 2018 15:01 |
Last Modified: |
05 Dec 2022 15:11 |
Publisher DOI: |
10.1038/ncomms15981 |
PubMed ID: |
28714471 |
BORIS DOI: |
10.7892/boris.112030 |
URI: |
https://boris.unibe.ch/id/eprint/112030 |
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