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Updated: May 30, 2025

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TOP2A inhibition and its cellular effects related to cell cycle checkpoint adaptation pathway

Maria Arroyo1, M A Fernández-Mimbrera2, E Gollini2

  • 1Cell Biology and Epigenetics, Department of Biology, Technical University of Darmstadt, Darmstadt, Germany. arroyo.lopez.mc@gmail.com.

Scientific Reports
|January 30, 2025
PubMed

Insights

This study explores how cells adapt to the Decatenation Checkpoint (DC) triggered by TOP2A inhibition. MCPH1 depletion was found to enhance DC robustness in p53-negative cells, impacting cell cycle dynamics.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Genetics

Background:

  • The Decatenation Checkpoint (DC) is activated by chromosome entanglements, often induced by TOP2A catalytic inhibition.
  • Checkpoint adaptation is the cell's ability to bypass or override the DC.
  • p53 and MCPH1 are known factors involved in checkpoint adaptation.

Purpose of the Study:

  • To investigate the role of MCPH1 in Decatenation Checkpoint (DC) adaptation.
  • To analyze the effects of p53 and MCPH1 depletion on cell cycle dynamics and adaptation.
  • To compare the cellular and transcriptional outcomes of different TOP2A inhibition mechanisms.

Main Methods:

  • Utilized hTERT-RPE1 cellular models with depletion of p53 or both p53 and MCPH1.
  • Analyzed cell cycle dynamics, adaptation, segregation defects, and apoptosis rates.
  • Examined transcriptional changes following prolonged exposure to TOP2A inhibitors.

Main Results:

  • MCPH1 depletion altered cell cycle dynamics compared to control cells.
  • MCPH1 depletion restored the robustness of the Decatenation Checkpoint (DC) in a p53-negative background.
  • Differential effects of TOP2A poisons versus catalytic inhibitors on cellular outcomes and transcriptional profiles were observed.

Conclusions:

  • MCPH1 plays a significant role in Decatenation Checkpoint (DC) regulation and adaptation.
  • The study highlights distinct cellular responses to different types of TOP2A inhibition.
  • Findings contribute to understanding the physiological implications of the DC and checkpoint adaptation in non-cancerous cells.
Keywords:
Checkpoint adaptationG2 checkpointICRF193MCPH1MicroscopyTOP2A inhibition

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