BACKGROUND: The genome is continuously attacked by a variety of agents that 
cause DNA damage. Recognition of DNA lesions activates the cellular DNA damage 
response (DDR), which comprises a network of signal transduction pathways to 
maintain genome integrity. In response to severe DNA damage, cells undergo 
apoptosis to avoid transformation into tumour cells, or alternatively, the cells 
enter permanent cell cycle arrest, called senescence. Most tumour cells have 
defects in pathways leading to DNA repair or apoptosis. In addition, apoptosis 
could be counteracted by nuclear factor kappa B (NF-κB), the main anti-apoptotic 
transcription factor in the DDR. Despite the high clinical relevance, the 
interplay of the DDR pathways is poorly understood. For therapeutic purposes DNA 
damage signalling processes are induced to induce apoptosis in tumour cells. 
However, the efficiency of radio- and chemotherapy is strongly hampered by cell 
survival pathways in tumour cells. In this study logical modelling was performed 
to facilitate understanding of the complexity of the signal transduction 
networks in the DDR and to provide cancer treatment options.
RESULTS: Our comprehensive discrete logical model provided new insights into the 
dynamics of the DDR in human epithelial tumours. We identified new mechanisms by 
which the cell regulates the dynamics of the activation of the tumour suppressor 
p53 and NF-κB. Simulating therapeutic intervention by agents causing DNA 
single-strand breaks (SSBs) or DNA double-strand breaks (DSBs) we identified 
candidate target proteins for sensitization of carcinomas to therapeutic 
intervention. Further, we enlightened the DDR in different genetic diseases, and 
by failure mode analysis we defined molecular defects putatively contributing to 
carcinogenesis.
CONCLUSION: By logic modelling we identified candidate target proteins that 
could be suitable for radio- and chemotherapy, and contributes to the design of 
more effective therapies.