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bioRxiv · 10.1101/2020.03.19.998674

Excessive E2F transcription in single cancer cells precludes transient cell cycle exit after DNA damage.

Segeren, H. S.·van Rijnberk, L. M.·Moreno, E.·Riemers, F. M.·Yuan, R.·Wubbolts, R.·de Bruin, A.·Westendorp, B.
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Abstract

E2F transcription factors control the expression of cell cycle genes. Cancers often demonstrate enhanced E2F target gene expression, which can be explained by increased percentages of replicating cells. However, we now demonstrate in human cancer biopsies that individual neoplastic cells display abnormally high levels of E2F-dependent transcription. To mimic this situation, we deleted the atypical E2F repressors (E2F7/8) in untransformed cells. Individual cells with elevated E2F-activity during S/G2-phase failed to exit the cell cycle after DNA damage and underwent mitosis. In contrast, wild type cells completed S-phase and then exit the cell cycle by activating the APC/CCdh1 via repression of the E2F-target Emi1. Strikingly, many arrested wildtype cells could eventually inactivate APC/CCdh1 to execute a second round of DNA replication and mitosis, thereby becoming tetraploid. Cells with elevated E2F-transcription fail to exit the cell cycle after DNA damage which potentially causes genomic instability, promotes malignant progression and reduces drug sensitivity.

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Segeren, H. S., van Rijnberk, L. M., Moreno, E., Riemers, F. M., Yuan, R., Wubbolts, R., de Bruin, A., Westendorp, B.. 2020-03-20. Excessive E2F transcription in single cancer cells precludes transient cell cycle exit after DNA damage.. https://doi.org/10.1101/2020.03.19.998674

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