TOP2A inhibition and its cellular effects related to cell cycle checkpoint adaptation pathway
Abstract In this study, we investigate the G2 checkpoint activated by chromosome entanglements, the so-called Decatenation Checkpoint (DC), which can be activated by TOP2A catalytic inhibition. Specifically, we focus on the spontaneous ability of cells to bypass or override this checkpoint, referred...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-01-01
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| Series: | Scientific Reports |
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| Online Access: | https://doi.org/10.1038/s41598-025-87895-8 |
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| author | Maria Arroyo M. A. Fernández-Mimbrera E. Gollini A. Esteve-Codina A. Sánchez Juan Alberto Marchal |
| author_facet | Maria Arroyo M. A. Fernández-Mimbrera E. Gollini A. Esteve-Codina A. Sánchez Juan Alberto Marchal |
| author_sort | Maria Arroyo |
| collection | DOAJ |
| description | Abstract In this study, we investigate the G2 checkpoint activated by chromosome entanglements, the so-called Decatenation Checkpoint (DC), which can be activated by TOP2A catalytic inhibition. Specifically, we focus on the spontaneous ability of cells to bypass or override this checkpoint, referred to as checkpoint adaptation. Some factors involved in adapting to this checkpoint are p53 and MCPH1. Using cellular models depleted of p53 or both p53 and MCPH1 in hTERT-RPE1 cells, we analyzed cell cycle dynamics and adaptation, segregation defects, apoptosis rate, and transcriptional changes related to prolonged exposure to TOP2A inhibitors. Our findings reveal that cell cycle dynamics are altered in MCPH1-depleted cells compared to control cells. We found that MCPH1 depletion can restore the robustness of the DC in a p53-negative background. Furthermore, this research highlights the differential effects of TOP2A poisons and catalytic inhibitors on cellular outcomes and transcriptional profiles. By examining the different mechanisms of TOP2A inhibition and their impact on cellular processes, this study contributes to a deeper understanding of the regulation and physiological implications of the DC and checkpoint adaptation in non-carcinogenic cell lines. |
| format | Article |
| id | doaj-art-2de56321e0ff4c698d4d28f739c45a9a |
| institution | OA Journals |
| issn | 2045-2322 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
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| series | Scientific Reports |
| spelling | doaj-art-2de56321e0ff4c698d4d28f739c45a9a2025-08-20T02:28:03ZengNature PortfolioScientific Reports2045-23222025-01-0115111910.1038/s41598-025-87895-8TOP2A inhibition and its cellular effects related to cell cycle checkpoint adaptation pathwayMaria Arroyo0M. A. Fernández-Mimbrera1E. Gollini2A. Esteve-Codina3A. Sánchez4Juan Alberto Marchal5Cell Biology and Epigenetics, Department of Biology, Technical University of DarmstadtDepartamento Biología Experimental, Universidad de JaénDepartamento Biología Experimental, Universidad de JaénCentre Nacional d’Anàlisi Genòmica (CNAG)Departamento Biología Experimental, Universidad de JaénDepartamento Biología Experimental, Universidad de JaénAbstract In this study, we investigate the G2 checkpoint activated by chromosome entanglements, the so-called Decatenation Checkpoint (DC), which can be activated by TOP2A catalytic inhibition. Specifically, we focus on the spontaneous ability of cells to bypass or override this checkpoint, referred to as checkpoint adaptation. Some factors involved in adapting to this checkpoint are p53 and MCPH1. Using cellular models depleted of p53 or both p53 and MCPH1 in hTERT-RPE1 cells, we analyzed cell cycle dynamics and adaptation, segregation defects, apoptosis rate, and transcriptional changes related to prolonged exposure to TOP2A inhibitors. Our findings reveal that cell cycle dynamics are altered in MCPH1-depleted cells compared to control cells. We found that MCPH1 depletion can restore the robustness of the DC in a p53-negative background. Furthermore, this research highlights the differential effects of TOP2A poisons and catalytic inhibitors on cellular outcomes and transcriptional profiles. By examining the different mechanisms of TOP2A inhibition and their impact on cellular processes, this study contributes to a deeper understanding of the regulation and physiological implications of the DC and checkpoint adaptation in non-carcinogenic cell lines.https://doi.org/10.1038/s41598-025-87895-8TOP2A inhibitionICRF193G2 checkpointCheckpoint adaptationMCPH1Microscopy |
| spellingShingle | Maria Arroyo M. A. Fernández-Mimbrera E. Gollini A. Esteve-Codina A. Sánchez Juan Alberto Marchal TOP2A inhibition and its cellular effects related to cell cycle checkpoint adaptation pathway Scientific Reports TOP2A inhibition ICRF193 G2 checkpoint Checkpoint adaptation MCPH1 Microscopy |
| title | TOP2A inhibition and its cellular effects related to cell cycle checkpoint adaptation pathway |
| title_full | TOP2A inhibition and its cellular effects related to cell cycle checkpoint adaptation pathway |
| title_fullStr | TOP2A inhibition and its cellular effects related to cell cycle checkpoint adaptation pathway |
| title_full_unstemmed | TOP2A inhibition and its cellular effects related to cell cycle checkpoint adaptation pathway |
| title_short | TOP2A inhibition and its cellular effects related to cell cycle checkpoint adaptation pathway |
| title_sort | top2a inhibition and its cellular effects related to cell cycle checkpoint adaptation pathway |
| topic | TOP2A inhibition ICRF193 G2 checkpoint Checkpoint adaptation MCPH1 Microscopy |
| url | https://doi.org/10.1038/s41598-025-87895-8 |
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