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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

DOI

10.1038/ncomms15981

Type

Journal article

Journal

Nat Commun

Publication Date

17/07/2017

Volume

8

Keywords

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