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MCPH1 Lack of Function Enhances Mitotic Cell Sensitivity Caused by Catalytic Inhibitors of Topo II

María Arroyo1, Antonio Sánchez1, Ana Cañuelo1

  • 1Department of Experimental Biology, University of Jaén, 23071 Jaén, Spain.

Genes
|April 12, 2020
PubMed

Insights

MCPH1 depletion increases cell death when Topoisomerase II (Topo II) activity is inhibited. Cells lacking MCPH1 function show heightened sensitivity to Topo II catalytic inhibition, leading to increased mitotic cell death.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Genetics

Background:

  • Topoisomerase II (Topo II) is crucial for resolving DNA catenations, ensuring accurate chromosome segregation during mitosis.
  • A G2 checkpoint monitors Topo II activity to prevent mitotic entry until decatenation is complete.
  • MCPH1 protein, mutated in primary microcephaly, is implicated in mitotic regulation, but its role in Topo II function was unclear.

Purpose of the Study:

  • To investigate whether MCPH1 deficiency impacts Topo II activity or sensitivity during mitosis.
  • To determine if MCPH1-depleted cells exhibit altered responses to Topo II catalytic inhibition.
  • To elucidate the role of MCPH1 in maintaining mitotic fidelity under Topo II stress.

Main Methods:

  • Live single-cell imaging of MCPH1-depleted HeLa cells undergoing mitosis.
  • Catalytic inhibition of Topoisomerase II (Topo II) to perturb DNA decatenation.
  • Assessment of chromosome alignment and segregation dynamics.
  • Analysis of mitotic cell death incidence and G2 arrest abrogation via Chk1 inhibition.

Main Results:

  • MCPH1-deficient cells did not show increased susceptibility to minor decatenation defects in chromosome alignment or segregation.
  • MCPH1-depleted cells exhibited a higher incidence of mitotic cell death when Topo II activity was catalytically inhibited.
  • Abrogation of the Topo II-induced G2 arrest by Chk1 inhibition further increased mitotic cell death in MCPH1-deficient cells.

Conclusions:

  • MCPH1 deficiency does not impair the G2 decatenation checkpoint but increases mitotic hypersensitivity to Topo II catalytic inhibition.
  • The absence of MCPH1 function sensitizes cells to Topo II activity perturbations, leading to elevated mitotic cell death.
  • MCPH1 plays a critical role in cellular resilience against Topo II-mediated mitotic stress.
Keywords:
ICRFMCPH1Topoisomerase IIanaphase errorschromosome condensationchromosome segregationdecatenation checkpointmitotic catastrophemitotic cell death

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