Journal
NATURE COMMUNICATIONS
Volume 8, Issue -, Pages -Publisher
NATURE PORTFOLIO
DOI: 10.1038/ncomms15981
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Funding
- Dutch Cancer Society [RUG 2011-5093, NKI 2011-5220]
- Netherlands Organization for Scientific Research [NWO-VIDI 916-76062]
- European Research Council [ERC-CoG-682421, ERC-CoG-681572]
- Swiss National Science Foundation [310030_156869]
- Swiss Cancer Research [MD-PhD-3446-01-2014]
- Cancer Research UK [22907] Funding Source: researchfish
- Swiss National Science Foundation (SNF) [310030_156869] Funding Source: Swiss National Science Foundation (SNF)
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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(-/-); p53(-/-) and Brca1(-/-); p53(-/-) mammary 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.
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