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Data from: Inhibitors of Rho kinases (ROCK) induce multiple mitotic defects and synthetic lethality in BRCA2-deficient cells

Martino, Julieta1; Siri, Sebastian1; Calzetta, Nicolás1; Paviolo, Natalia1; Garro, Cintia2; Pansa, María2; Carbajosa, Sofía2; Brown, Aaron3; Bocco, José2; Gloger, Israel4; Drewes, Gerard4; Madauss, Kevin4; Soria, Gastón2; Gottifredi, Vanesa1

Published Apr 13, 2026 on Dryad. https://doi.org/10.5061/dryad.ht76hdrjj

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Apr 13, 2026 version files 1.03 GB

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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 mitotic 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.