TY - JOUR
T1 - Excessive E2F Transcription in Single Cancer Cells Precludes Transient Cell-Cycle Exit after DNA Damage
AU - Segeren, Hendrika A.
AU - van Rijnberk, Lotte M.
AU - Moreno, Eva
AU - Riemers, Frank M.
AU - van Liere, Elsbeth A.
AU - Yuan, Ruixue
AU - Wubbolts, Richard
AU - de Bruin, Alain
AU - Westendorp, Bart
PY - 2020/12/1
Y1 - 2020/12/1
N2 - 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/C-Cdh1 via repression of the E2F target Emi1. Many arrested wild-type cells eventually inactivate APC/C-Cdh1 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.
AB - 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/C-Cdh1 via repression of the E2F target Emi1. Many arrested wild-type cells eventually inactivate APC/C-Cdh1 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.
U2 - 10.1016/j.celrep.2020.108449
DO - 10.1016/j.celrep.2020.108449
M3 - Article
SN - 2211-1247
VL - 33
SP - 1
EP - 20
JO - Cell reports
JF - Cell reports
IS - 9
M1 - 108449
ER -