title: A novel mathematical model of ATM/p53/NF- κB pathways points to the importance of the DDR switch-off mechanisms.
abstract: Ataxia telangiectasia mutated (ATM) is a detector of double-strand breaks (DSBs) and a crucial component of the DNA damage response (DDR) along with p53 and NF- κB transcription factors and Wip1 phosphatase. Despite the recent advances in studying the DDR, the mechanisms of cell fate determination after DNA damage induction is still poorly understood.
  
  
  
  To investigate the importance of various DDR elements with particular emphasis on Wip1, we developed a novel mathematical model of ATM/p53/NF- κB pathways. Our results from in silico and in vitro experiments performed on U2-OS cells with Wip1 silenced to 25 % (Wip1-RNAi) revealed a strong dependence of cellular response to DNA damages on this phosphatase. Notably, Wip1-RNAi cells exhibited lower resistance to ionizing radiation (IR) resulting in smaller clonogenicity and higher apoptotic fraction.
  
  
  
  In this article, we demonstrated that Wip1 plays a role as a gatekeeper of apoptosis and influences the pro-survival behaviour of cells - the level of Wip1 increases to block the apoptotic decision when DNA repair is successful. Moreover, we were able to verify the dynamics of proteins and transcripts, apoptotic fractions and cells viability obtained from stochastic simulations using in vitro approaches. Taken together, we demonstrated that the model can be successfully used in prediction of cellular behaviour after exposure to IR. Thus, our studies may provide further insights into key elements involved in the underlying mechanisms of the DDR.
authors.affiliation: Faculty of Automatic Control, Electronics and Computer Science, Silesian University of Technology, Akademicka, Gliwice, 16, 44-100, Poland.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Jonak
authors.affiliation: Faculty of Automatic Control, Electronics and Computer Science, Silesian University of Technology, Akademicka, Gliwice, 16, 44-100, Poland.
authors.forename: Monika
authors.initials: M
authors.lastname: Kurpas
authors.affiliation: Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Wybrzeze Armii Krajowej, Gliwice, 15, 44-400, Poland.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Szoltysek
authors.affiliation: Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Wybrzeze Armii Krajowej, Gliwice, 15, 44-400, Poland.
authors.forename: Patryk
authors.initials: P
authors.lastname: Janus
authors.affiliation: Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Wybrzeze Armii Krajowej, Gliwice, 15, 44-400, Poland.
authors.forename: Agata
authors.initials: A
authors.lastname: Abramowicz
authors.affiliation: Faculty of Automatic Control, Electronics and Computer Science, Silesian University of Technology, Akademicka, Gliwice, 16, 44-100, Poland. krzysztof.puszynski@polsl.pl.
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Puszynski
mesh_terms: D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival; D004249:DNA Damage; D006801:Humans; D007700:Kinetics; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism*; D000071636:Protein Phosphatase 2C / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D016328:NF-kappa B; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; D064007:Ataxia Telangiectasia Mutated Proteins; C000607458:PPM1D protein, human; D000071636:Protein Phosphatase 2C
keywords: ATM; DNA damage; Deterministic; Mathematical; Model; Stochastic; Wip1; p53