The trapping of Poly-ADP-ribose polymerase (PARP) on DNA caused by PARP inhibitors (PARPi) triggers acute DNA replication stress and synthetic lethality (SL) in BRCA2-deficient cells. Hence, DNA damage is accepted as a prerequisite for SL in BRCA2-deficient cells. In contrast, here we show that inhibiting ROCK in BRCA2-deficient cells triggers SL independently from acute replication stress. Such SL is preceded by polyploidy and binucleation resulting from cytokinesis failure. Such initial mitosis abnormalities are followed by other M-phase defects, including anaphase bridges and abnormal mitotic figures associated with multipolar spindles, supernumerary centrosomes and multinucleation. SL was also triggered by inhibiting Citron Rho-interacting kinase, another enzyme that, similarly to ROCK, regulates cytokinesis. Together, these observations demonstrate that cytokinesis failure triggers mitotic abnormalities and SL in BRCA2-deficient cells. Furthermore, the prevention of mitotic entry by depletion of Early mitotic inhibitor 1 (EMI1) augmented the survival of BRCA2-deficient cells treated with ROCK inhibitors, thus reinforcing the association between M-phase and cell death in BRCA2-deficient cells. This novel SL differs from the one triggered by PARPi and uncovers mitosis as an Achilles heel of BRCA2-deficient cells.
All data generated or analysed during this study are included in the manuscript and supporting file
Inhibitors of ROCK kinases induce multiple mitotic defects and synthetic lethality in BRCA2-deficient cellsDryad Digital Repository, doi:10.5061/dryad.bcc2fqzfz.
Phenotypic screening assay on co-culture BRCA-proficient and BRCA -deficient cell lines.Dryad Digital Repository, doi:10.5061/dryad.ht76hdrjj.
- José Luis Bocco
- Gastón Soria
- José Luis Bocco
- Gastón Soria
- Vanesa Gottifredi
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
- Robert W. Sobol, Brown University, United States
© 2023, Martino et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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