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Martino, Julieta; Siri, Sebastián Omar; Calzetta, Nicolás Luis; Paviolo, Natalia Soledad; Garro, Cintia; Pansa, Maria F; Carbajosa, Sofía; Brown, Aaron C; Bocco, José Luis; Gloger, Israel; Drewes, Gerard; Madauss, Kevin P; Soria, Gastón; Gottifredi, Vanesa

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

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  • Media type: E-Article
  • Title: Inhibitors of Rho kinases (ROCK) induce multiple mitotic defects and synthetic lethality in BRCA2-deficient cells
  • Contributor: Martino, Julieta; Siri, Sebastián Omar; Calzetta, Nicolás Luis; Paviolo, Natalia Soledad; Garro, Cintia; Pansa, Maria F; Carbajosa, Sofía; Brown, Aaron C; Bocco, José Luis; Gloger, Israel; Drewes, Gerard; Madauss, Kevin P; Soria, Gastón; Gottifredi, Vanesa
  • Published: eLife Sciences Publications, Ltd, 2023
  • Published in: eLife, 12 (2023)
  • Language: English
  • DOI: 10.7554/elife.80254
  • ISSN: 2050-084X
  • Origination:
  • Footnote:
  • Description: 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.
  • Access State: Open Access