A predictive mathematical model of the DNA damage G2 checkpoint

J Theor Biol. 2013 Mar 7;320:159-69. doi: 10.1016/j.jtbi.2012.12.011. Epub 2012 Dec 22.


A predictive mathematical model of the transition from the G2 phase in the cell cycle to mitosis (M) was constructed from the known interactions of the proteins that are thought to play significant roles in the G2 to M transition as well as the DNA damage- induced G2 checkpoint. The model simulates the accumulation of active cyclin B1/Cdk1 (MPF) complexes in the nucleus to activate mitosis, the inhibition of this process by DNA damage, and transport of component proteins between cytoplasm and nucleus. Interactions in the model are based on activities of individual phospho-epitopes and binding sites of proteins involved in G2/M. Because tracking phosphoforms leads to combinatorial explosion, we employ a rule-based approach using the BioNetGen software. The model was used to determine the effects of depletion or over-expression of selected proteins involved in the regulation of the G2 to M transition in the presence and absence of DNA damage. Depletion of Plk1 delayed mitotic entry and recovery from the DNA damage-induced G2 arrest and over-expression of MPF attenuated the DNA damage-induced G2 delay. The model recapitulates the G2 delay observed in the biological response to varying levels of a DNA damage signal. The model produced the novel prediction that depletion of pkMyt1 results in an abnormal biological state in which G2 cells with DNA damage accumulate inactive nuclear MPF. Such a detailed model may prove useful for predicting DNA damage G2 checkpoint function in cancer and, therefore, sensitivity to cancer therapy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • CDC2 Protein Kinase / genetics
  • CDC2 Protein Kinase / metabolism
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism
  • Cell Nucleus / genetics
  • Cell Nucleus / metabolism*
  • Cyclin B1 / genetics
  • Cyclin B1 / metabolism
  • DNA Damage*
  • G2 Phase Cell Cycle Checkpoints*
  • Mitosis*
  • Models, Biological*
  • Neoplasms / genetics
  • Neoplasms / metabolism
  • Neoplasms / therapy
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism
  • Signal Transduction / genetics
  • Software*


  • Cell Cycle Proteins
  • Cyclin B1
  • Proto-Oncogene Proteins
  • Protein Serine-Threonine Kinases
  • polo-like kinase 1
  • CDC2 Protein Kinase