Inhibitors of Rho kinases (ROCK) induce multiple mitotic defects and synthetic lethality in BRCA2-deficient cells
- Fundación Instituto Leloir-CONICET, Argentina
- Universidad Nacional de Córdoba, Argentina
- Maine Medical Center Research Institute, United States
- GlaxoSmithKline, United States
- GlaxoSmithKline, United Kingdom
Abstract
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.
Data availability
All data generated or analysed during this study are included in the manuscript and supporting file
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Inhibitors of ROCK kinases induce multiple mitotic defects and synthetic lethality in BRCA2-deficient cellsDryad Digital Repository, doi:10.5061/dryad.bcc2fqzfz.
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Phenotypic screening assay on co-culture BRCA-proficient and BRCA -deficient cell lines.Dryad Digital Repository, doi:10.5061/dryad.ht76hdrjj.
Article and author information
Author details
Funding
GlaxoSmithKline (PAE-GLAXO 2014-0005)
- José Luis Bocco
GlaxoSmithKline (PCE-GSK 2017-0032)
- Gastón Soria
Fondo para la Investigación Científica y Tecnológica
- José Luis Bocco
- Gastón Soria
Agencia Nacional de Promoción Científica y Tecnológica (PICT 2018-01857)
- Vanesa Gottifredi
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Robert W. Sobol, Brown University, United States
Version history
- Received: May 13, 2022
- Preprint posted: June 28, 2022 (view preprint)
- Accepted: April 18, 2023
- Accepted Manuscript published: April 19, 2023 (version 1)
- Version of Record published: May 15, 2023 (version 2)
Copyright
© 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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Inhibitors of Rho kinases (ROCK) induce multiple mitotic defects and synthetic lethality in BRCA2-deficient cells
eLife 12:e80254.
https://doi.org/10.7554/eLife.80254
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