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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.

Original publication




Journal article


Nat Commun

Publication Date





Anaphase, Animals, BRCA1 Protein, BRCA2 Protein, Breast Neoplasms, Cell Line, Tumor, Cytokinesis, DNA Damage, Female, HeLa Cells, Humans, Mammary Neoplasms, Animal, Mammary Neoplasms, Experimental, Mice, Mice, Knockout, Mitosis, Poly(ADP-ribose) Polymerase Inhibitors, Recombinational DNA Repair, Tumor Suppressor Protein p53, Tumor Suppressor Proteins