Abstract
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 language | English |
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Article number | 15981 |
Number of pages | 13 |
Journal | Nature Communications |
Volume | 8 |
DOIs | |
Publication status | Published - 17-Jul-2017 |
Keywords
- ADP-RIBOSE POLYMERASE
- STRAND BREAK REPAIR
- FANCONI-ANEMIA
- POLY(ADP-RIBOSE) POLYMERASE
- BRCA2-DEFICIENT TUMORS
- SYNTHETIC LETHALITY
- SUSCEPTIBILITY GENE
- MAMMARY-TUMORS
- FRAGILE SITES
- REPLICATION