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

2020 ◽  
Author(s):  
Hendrika A. Segeren ◽  
Lotte van Rijnberk ◽  
Eva Moreno ◽  
Frank Riemers ◽  
Ruixue Yuan ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Cancer Cells ◽  
Cell Cycle Exit ◽  
Single Cancer

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

Cell Reports ◽  
2020 ◽  
Vol 33 (9) ◽  
pp. 108449
Author(s):  
Hendrika A. Segeren ◽  
Lotte M. van Rijnberk ◽  
Eva Moreno ◽  
Frank M. Riemers ◽  
Elsbeth A. van Liere ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Cancer Cells ◽  
Cell Cycle Exit ◽  
Single Cancer

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

2020 ◽  
Author(s):  
Hendrika A. Segeren ◽  
Lotte M. van Rijnberk ◽  
Eva Moreno ◽  
Frank M. Riemers ◽  
Ruixue Yuan ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Target Gene ◽  
Human Cancer ◽  
Cell Cycle Exit ◽  
Wild Type ◽  
Cell Cycle Genes ◽  
Single Cancer ◽  
G2 Phase ◽  
E2f Transcription Factors

AbstractE2F 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.

scholarly journals Role of the circadian clock "Death-Loop" in the DNA damage response underpinning cancer treatment resistance

2022 ◽  
Author(s):  
Ninel Miriam Vainshelbaum ◽  
Kristine Salmina ◽  
Bogdan I Gerashchenko ◽  
Marija Lazovska ◽  
Pawel Zayakin ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Circadian Clock ◽  
Cancer Cells ◽  
Dna Damage Response ◽  
Embryonic Stem ◽  
Early Embryo ◽  
Mitotic Slippage ◽  
Damage Response ◽  
Telomere Regulation

The Circadian Clock (CC) drives the normal cell cycle and reciprocally regulates telomere elongation. However, it can be deregulated in cancer, embryonic stem cells (ESC) and the early embryo. Here, its role in the resistance of cancer cells to genotoxic treatments was assessed in relation to whole-genome duplication (WGD) and telomere regulation. We first evaluated the DNA damage response of polyploid cancer cells and observed a similar impact on the cell cycle to that seen in ESC - overcoming G1/S, adapting DNA damage checkpoints, tolerating DNA damage, and coupling telomere erosion to accelerated cell senescence, favouring transition by mitotic slippage into the ploidy cycle (reversible polyploidy). Next, we revealed a positive correlation between cancer WGD and deregulation of CC assessed by bioinformatics on 11 primary cancer datasets (rho=0.83; p<0.01). As previously shown, the cancer cells undergoing mitotic slippage cast off telomere fragments with TERT, restore the telomeres by recombination and return their depolyploidised mitotic offspring to TERT-dependent telomere regulation. Through depolyploidisation and the CC "death loop", the telomeres and Hayflick limit count are thus again renewed. This mechanism along with similar inactivity of the CC in early embryos supports a life-cycle (embryonic) concept of cancer.

scholarly journals Large-Scale Image Analysis for Investigating Spatio-Temporal Changes in Nuclear DNA Damage Caused by Nitrogen Atmospheric Pressure Plasma Jets

2020 ◽  
Vol 21 (11) ◽  
pp. 4127
Author(s):  
Xu Han ◽  
James Kapaldo ◽  
Yueying Liu ◽  
M. Sharon Stack ◽  
Elahe Alizadeh ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Image Analysis ◽  
Cancer Cells ◽  
Atmospheric Pressure ◽  
Large Scale ◽  
Nuclear Dna ◽  
Atmospheric Pressure Plasma ◽  
Plasma Jet ◽  
Spatio Temporal

The effective clinical application of atmospheric pressure plasma jet (APPJ) treatments requires a well-founded methodology that can describe the interactions between the plasma jet and a treated sample and the temporal and spatial changes that result from the treatment. In this study, we developed a large-scale image analysis method to identify the cell-cycle stage and quantify damage to nuclear DNA in single cells. The method was then tested and used to examine spatio-temporal distributions of nuclear DNA damage in two cell lines from the same anatomic location, namely the oral cavity, after treatment with a nitrogen APPJ. One cell line was malignant, and the other, nonmalignant. The results showed that DNA damage in cancer cells was maximized at the plasma jet treatment region, where the APPJ directly contacted the sample, and declined radially outward. As incubation continued, DNA damage in cancer cells decreased slightly over the first 4 h before rapidly decreasing by approximately 60% at 8 h post-treatment. In nonmalignant cells, no damage was observed within 1 h after treatment, but damage was detected 2 h after treatment. Notably, the damage was 5-fold less than that detected in irradiated cancer cells. Moreover, examining damage with respect to the cell cycle showed that S phase cells were more susceptible to DNA damage than either G1 or G2 phase cells. The proposed methodology for large-scale image analysis is not limited to APPJ post-treatment applications and can be utilized to evaluate biological samples affected by any type of radiation, and, more so, the cell-cycle classification can be used on any cell type with any nuclear DNA staining.

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