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

Autor:	Martino J; Fundación Instituto Leloir-CONICET, Buenos Aires, Argentina., Siri SO; Fundación Instituto Leloir-CONICET, Buenos Aires, Argentina., Calzetta NL; Fundación Instituto Leloir-CONICET, Buenos Aires, Argentina., Paviolo NS; Fundación Instituto Leloir-CONICET, Buenos Aires, Argentina., Garro C; Centro de Investigaciones en Bioquímica Clínica e Inmunología, CIBICI-CONICET, Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina.; OncoPrecision, Córdoba, Argentina., Pansa MF; Centro de Investigaciones en Bioquímica Clínica e Inmunología, CIBICI-CONICET, Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina., Carbajosa S; Centro de Investigaciones en Bioquímica Clínica e Inmunología, CIBICI-CONICET, Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina.; OncoPrecision, Córdoba, Argentina., Brown AC; Center for Molecular Medicine, Maine Medical Center Research Institute, Scarborough, United States., Bocco JL; Centro de Investigaciones en Bioquímica Clínica e Inmunología, CIBICI-CONICET, Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina., Gloger I; GlaxoSmithKline-Trust in Science, Global Health R&D, Stevenage, United Kingdom., Drewes G; GlaxoSmithKline-Trust in Science, Global Health R&D, Stevenage, United Kingdom., Madauss KP; GlaxoSmithKline-Trust in Science, Global Health R&D, Upper Providence, United States., Soria G; Centro de Investigaciones en Bioquímica Clínica e Inmunología, CIBICI-CONICET, Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina.; OncoPrecision, Córdoba, Argentina., Gottifredi V; Fundación Instituto Leloir-CONICET, Buenos Aires, Argentina.
Jazyk:	angličtina
Zdroj:	ELife [Elife] 2023 Apr 19; Vol. 12. Date of Electronic Publication: 2023 Apr 19.
DOI:	10.7554/eLife.80254
Abstrakt:	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. Competing Interests: JM, SS, NC, NP, CG, SC, AB, JB, GS, VG No competing interests declared, MP, IG, GD, KM is affiliated with GlaxoSmithKline and has no other competing interests to declare (© 2023, Martino, Siri et al.)
Databáze:	MEDLINE
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