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

• DOI: 10.7554/elife.80254
• Publication Date: 2023-04-19T12:00:31Z
• Authors: Julieta Martino; Sebastián Omar Siri; Nicolás Luis Calz...; Natalia Soledad P...; Cintia Garro; Maria F Pansa; Sofía Carbajosa; Aaron C Brown; José Luis Bocco; Israel Gloger; Gerard Drewes; Kevin P Madauss; Gastón Soria; Vanesa Gottifredi
• Keywords: Mitotic catastrophe; Mitotic exit

The trapping of Poly-ADP-ribose polymerase (PARP) on DNA caused by PARP inhibitors (PARPi) triggers acute replication stress and synthetic lethality (SL) in BRCA2-deficient cells. Hence, damage is accepted as a prerequisite for SL In contrast, here we show that inhibiting ROCK cells independently from stress. Such preceded polyploidy binucleation resulting cytokinesis failure. initial mitosis abnormalities are followed other M phase defects, including anaphase bridges abnormal mitotic figures associated with multipolar spindles, supernumerary centrosomes multinucleation. was also triggered Citron Rho-interacting kinase, another enzyme that, similarly to ROCK, regulates cytokinesis. Together, these observations demonstrate failure Furthermore, the prevention entry depletion Early inhibitor 1 (EMI1) augmented survival treated inhibitors, thus reinforcing association between cell death This novel differs one PARPi uncovers an Achilles heel