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

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.