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.

Highlights

  • The G2/M DNA damage checkpoint is an essential control mechanism in cell cycle regulation

  • They demonstrated that DNA damage occurs at the first S phase following Plk[1] depletion and the response is more severe in Plk1depleted p53-null cancer cells

  • To build the computational model of molecular mechanism of the G2/M DNA damage checkpoint regulation in cancer cells, we gathered relevant molecular interaction data from the published in Fig. 1, ATM/ATR checkpoint activation downregulates M-phase inducer phosphatase Cdc2527, activates tumor suppresser protein p5328, and inhibits Plk[1] activity29. p53 is a transcription literature

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Summary

Introduction

The G2/M DNA damage checkpoint is an essential control mechanism in cell cycle regulation. Liu and co-workers[5] have shown that depletion of Plk[1] in p53-null cancer cells promotes the activation of DNA damage checkpoint and induces G2/M arrest and apoptosis. Yim and Erikson[8] have determined that Plk[1] depletion induces DNA damage in both S and G2/M cell cycle phases with the effect in G2/M being more pronounced. They demonstrated that DNA damage occurs at the first S phase following Plk[1] depletion and the response is more severe in Plk1depleted p53-null cancer cells. The exact mechanism that is responsible for this arrest and associated apoptosis in Plk1-depleted cancer cells remains unknown

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