Excessive E2F Transcription in Single Cancer Cells Precludes Transient Cell-Cycle Exit after DNA Damage

• Published in: Cell reports (Cambridge) 2020-12, Vol.33 (9), p.108449-108449, Article 108449
• Main Authors: Segeren, Hendrika A., van Rijnberk, Lotte M., Moreno, Eva, Riemers, Frank M., van Liere, Elsbeth A., Yuan, Ruixue, Wubbolts, Richard, de Bruin, Alain, Westendorp, Bart
• Format: Article
• Language: English
• Subjects: anaphase-promoting complex/cyclosome; cancer; Cell Cycle; DNA damage; DNA Damage - genetics; E2F transcription; E2F Transcription Factors - metabolism; Emi1; Humans; live-cell imaging; P53; Sequence Analysis, RNA - methods; single-cell RNA sequencing; tetraploidy
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2020.108449

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 demonstrate in human cancer biopsy specimens that individual neoplastic cells display abnormally high levels of E2F-dependent transcription. To mimic this situation, we delete the atypical E2F repressors (E2F7/8) or overexpress the E2F3 activator in untransformed cells. Cells with elevated E2F activity during S/G2 phase fail to exit the cell cycle after DNA damage and undergo mitosis. In contrast, wild-type cells complete S phase and then exit the cell cycle by activating the APC/CCdh1 via repression of the E2F target Emi1. Many arrested wild-type cells 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. [Display omitted] •Individual cycling cancer cells display enhanced E2F target gene expression•E2F7/8 deletion or E2F3 overexpression overrides cell-cycle exit after DNA damage•Elevated levels of the E2F target Emi1 prevent DNA-damage-induced cell-cycle exit•The cell-cycle exit after DNA damage is transient and leads to endoreplication Segeren et al. demonstrate that cycling human cancer cells exhibit abnormally high E2F target gene expression. Healthy cells can activate APC/CCdh1 after DNA damage to allow a transient cell-cycle exit. However, elevated transcription of the E2F target Emi1 forces cells to progress to mitosis and potentially promotes genomic instability.