E2F activity determines mitosis versus whole-genome duplication in G2-arrested cells
Abstract While mitogenic signaling is known to regulate cell-cycle entry during the G1 phase, its function in the G2 phase remains elusive. Here we show that mitogenic signaling controls whether G2-arrested cells proceed through mitosis or undergo whole-genome duplication. Although mitogenic signali...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-07-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-62061-w |
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| author | Kibum Kim Jessica Armand Sungsoo Kim Hee Won Yang |
| author_facet | Kibum Kim Jessica Armand Sungsoo Kim Hee Won Yang |
| author_sort | Kibum Kim |
| collection | DOAJ |
| description | Abstract While mitogenic signaling is known to regulate cell-cycle entry during the G1 phase, its function in the G2 phase remains elusive. Here we show that mitogenic signaling controls whether G2-arrested cells proceed through mitosis or undergo whole-genome duplication. Although mitogenic signaling is not required for the G2/M transition under normal conditions, it modulates E2F transcriptional activity via c-Myc. When G2 arrest occurs due to CDK4/6 and CDK2 suppression, E2F activity levels determine the status of APC/C inactivation and the CDK2-Rb feedback loop. Upon release from G2 arrest, cells maintaining APC/C inactivation promptly induce CDK2 activation and FoxM1 phosphorylation, driving mitotic entry. Conversely, APC/C reactivation degrades cyclin A and abolishes the CDK2-Rb loop, necessitating CDK4/6 activation for cell-cycle re-entry. This regulatory mechanism mirrors the G1-phase process, resulting in whole-genome duplication. In cancer cells, this process promotes genome instability and oncogene amplification, contributing to aggressive behavior. These findings reveal a previously unrecognized mitogen-dependent checkpoint that governs cell fate in the G2 phase. |
| format | Article |
| id | doaj-art-cc586d8610f64a3a8d2f651a02d6deaa |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-cc586d8610f64a3a8d2f651a02d6deaa2025-08-20T03:43:16ZengNature PortfolioNature Communications2041-17232025-07-0116111310.1038/s41467-025-62061-wE2F activity determines mitosis versus whole-genome duplication in G2-arrested cellsKibum Kim0Jessica Armand1Sungsoo Kim2Hee Won Yang3Department of Pathology and Cell Biology, Columbia UniversityDepartment of Pathology and Cell Biology, Columbia UniversityDepartment of Pathology and Cell Biology, Columbia UniversityDepartment of Pathology and Cell Biology, Columbia UniversityAbstract While mitogenic signaling is known to regulate cell-cycle entry during the G1 phase, its function in the G2 phase remains elusive. Here we show that mitogenic signaling controls whether G2-arrested cells proceed through mitosis or undergo whole-genome duplication. Although mitogenic signaling is not required for the G2/M transition under normal conditions, it modulates E2F transcriptional activity via c-Myc. When G2 arrest occurs due to CDK4/6 and CDK2 suppression, E2F activity levels determine the status of APC/C inactivation and the CDK2-Rb feedback loop. Upon release from G2 arrest, cells maintaining APC/C inactivation promptly induce CDK2 activation and FoxM1 phosphorylation, driving mitotic entry. Conversely, APC/C reactivation degrades cyclin A and abolishes the CDK2-Rb loop, necessitating CDK4/6 activation for cell-cycle re-entry. This regulatory mechanism mirrors the G1-phase process, resulting in whole-genome duplication. In cancer cells, this process promotes genome instability and oncogene amplification, contributing to aggressive behavior. These findings reveal a previously unrecognized mitogen-dependent checkpoint that governs cell fate in the G2 phase.https://doi.org/10.1038/s41467-025-62061-w |
| spellingShingle | Kibum Kim Jessica Armand Sungsoo Kim Hee Won Yang E2F activity determines mitosis versus whole-genome duplication in G2-arrested cells Nature Communications |
| title | E2F activity determines mitosis versus whole-genome duplication in G2-arrested cells |
| title_full | E2F activity determines mitosis versus whole-genome duplication in G2-arrested cells |
| title_fullStr | E2F activity determines mitosis versus whole-genome duplication in G2-arrested cells |
| title_full_unstemmed | E2F activity determines mitosis versus whole-genome duplication in G2-arrested cells |
| title_short | E2F activity determines mitosis versus whole-genome duplication in G2-arrested cells |
| title_sort | e2f activity determines mitosis versus whole genome duplication in g2 arrested cells |
| url | https://doi.org/10.1038/s41467-025-62061-w |
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