MCPH1 Lack of Function Enhances Mitotic Cell Sensitivity Caused by Catalytic Inhibitors of Topo II.
Genes (Basel)
; 11(4)2020 04 08.
Article
en En
| MEDLINE
| ID: mdl-32276518
ABSTRACT
The capacity of Topoisomerase II (Topo II) to remove DNA catenations that arise after replication is essential to ensure faithful chromosome segregation. Topo II activity is monitored during G2 by a specific checkpoint pathway that delays entry into mitosis until the chromosomes are properly decatenated. Recently, we demonstrated that the mitotic defects that are characteristic of cells depleted of MCPH1 function, a protein mutated in primary microcephaly, are not a consequence of a weakened G2 decatenation checkpoint response. However, the mitotic defects could be accounted for by a minor defect in the activity of Topo II during G2/M. To test this hypothesis, we have tracked at live single cell resolution the dynamics of mitosis in MCPH1 depleted HeLa cells upon catalytic inhibition of Topo II. Our analyses demonstrate that neither chromosome alignment nor segregation are more susceptible to minor perturbation in decatenation in MCPH1 deficient cells, as compared with control cells. Interestingly, MCPH1 depleted cells were more prone to mitotic cell death when decatenation was perturbed. Furthermore, when the G2 arrest that was induced by catalytic inhibition of Topo II was abrogated by Chk1 inhibition, the incidence of mitotic cell death was also increased. Taken together, our data suggest that the MCPH1 lack of function increases mitotic cell hypersensitivity to the catalytic inhibition of Topo II.
Palabras clave
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
ADN-Topoisomerasas de Tipo II
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Proteínas de Ciclo Celular
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Proteínas del Citoesqueleto
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Puntos de Control de la Fase G2 del Ciclo Celular
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Mitosis
Tipo de estudio:
Diagnostic_studies
Límite:
Humans
Idioma:
En
Revista:
Genes (Basel)
Año:
2020
Tipo del documento:
Article
País de afiliación:
España