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Crosstalk between Plk1, p53, cell cycle, and G2/M DNA damage checkpoint regulation in cancer: computational modeling
Yongwoon Jung1, Pavel Kraikivski2, Sajad Shafiekhani3
1Department of Biomedical Engineering, Medical College of Wisconsin, Milwaukee, WI, 53226, USA.
Abstract:
Different cancer cell lines can have varying responses to the same perturbations or stressful conditions. Cancer cells that have DNA damage checkpoint-related mutations are often more sensitive to gene perturbations including altered Plk1 and p53 activities than cancer cells without these mutations. The perturbations often induce a cell cycle arrest in the former cancer, whereas they only delay the cell cycle progression in the latter cancer. To study crosstalk between Plk1, p53, and G2/M DNA damage checkpoint leading to differential cell cycle regulations, we developed a computational model by extending our recently developed model of mitotic cell cycle and including these key interactions. We have used the model to analyze the cancer cell cycle progression under various gene perturbations including Plk1-depletion conditions. We also analyzed mutations and perturbations in approximately 1800 different cell lines available in the Cancer Dependency Map and grouped lines by genes that are represented in our model. Our model successfully explained phenotypes of various cancer cell lines under different gene perturbations. Several sensitivity analysis approaches were used to identify the range of key parameter values that lead to the cell cycle arrest in cancer cells. Our resulting model can be used to predict the effect of potential treatments targeting key mitotic and DNA damage checkpoint regulators on cell cycle progression of different types of cancer cells.
Insights
Computational modeling reveals how DNA damage checkpoint mutations affect cancer cell cycle responses to gene perturbations. This helps predict how treatments targeting cell cycle regulators may impact different cancer types.
Area of Science:
- Computational biology
- Cancer research
- Cell cycle regulation
Background:
- Cancer cell responses vary based on genetic mutations, particularly those affecting DNA damage checkpoints.
- Cells with DNA damage checkpoint mutations exhibit heightened sensitivity to perturbations in genes like Plk1 and p53, leading to cell cycle arrest.
Purpose of the Study:
- To investigate the intricate crosstalk between Plk1, p53, and the G2/M DNA damage checkpoint.
- To develop a computational model for analyzing differential cell cycle regulation in cancer cells under various conditions.
Main Methods:
- Extended a pre-existing mitotic cell cycle model to incorporate Plk1, p53, and DNA damage checkpoint interactions.
- Analyzed approximately 1800 cancer cell lines from the Cancer Dependency Map, focusing on mutations and gene perturbations relevant to the model.
- Employed sensitivity analysis to pinpoint critical parameter values inducing cell cycle arrest.
Main Results:
- The developed computational model successfully replicated observed phenotypes of diverse cancer cell lines under different gene perturbations.
- Identified key parameter ranges essential for triggering cell cycle arrest in cancer cells.
- Demonstrated the model's capability to explain differential cell cycle regulation based on genetic backgrounds.
Conclusions:
- The model provides a robust framework for understanding cancer cell cycle dynamics in response to genetic alterations and perturbations.
- It can predict the efficacy of potential therapeutic strategies targeting mitotic and DNA damage checkpoint regulators.
- This approach facilitates personalized treatment predictions for various cancer types.
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