title: Modelling the onset of senescence at the G1/S cell cycle checkpoint.
abstract: BACKGROUND
  DNA damage (single or double-strand breaks) triggers adapted cellular responses. These responses are elicited through signalling pathways, which activate cell cycle checkpoints and basically lead to three cellular fates: cycle arrest promoting DNA repair, senescence (permanent arrest) or cell death. Cellular senescence is known for having a tumour-suppressive function and its regulation arouses a growing scientific interest. Here, we advance a qualitative model covering DNA damage response pathways, focusing on G1/S checkpoint enforcement, supposedly more sensitive to arrest than G2/M checkpoint.
  
  
  RESULTS
  We define a discrete, logical model encompassing ATM (ataxia telangiectasia mutated) and ATR (ATM and Rad3-related) pathways activation upon DNA damage, as well as G1/S checkpoint main components. It also includes the stress responsive protein p38MAPK (mitogen-activated protein kinase 14) known to be involved in the regulation of senescence. The model has four outcomes that convey alternative cell fates: proliferation, (transient) cell cycle arrest, apoptosis and senescence. Different levels of DNA damage are considered, defined by distinct combinations of single and double-strand breaks. Each leads to a single stable state denoting the cell fate adopted upon this specific damage. A range of model perturbations corresponding to gene loss-of-function or gain-of-function is compared to experimental mutations.
  
  
  CONCLUSIONS
  As a step towards an integrative model of DNA-damage response pathways to better cover the onset of senescence, our model focuses on G1/S checkpoint enforcement. This model qualitatively agrees with most experimental observations, including experiments involving mutations. Furthermore, it provides some predictions.
authors.forename: José C M
authors.initials: JC
authors.lastname: Mombach
authors.forename: Cristhian A
authors.initials: CA
authors.lastname: Bugs
authors.forename: Claudine
authors.initials: C
authors.lastname: Chaouiya
mesh_terms: D017209:Apoptosis / Q000235:genetics; D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism; D016922:Cellular Senescence / Q000235:genetics; D004249:DNA Damage; D004260:DNA Repair / Q000235:genetics; D059585:G1 Phase Cell Cycle Checkpoints / Q000235:genetics; D006801:Humans; D048308:Mitogen-Activated Protein Kinase 14 / Q000378:metabolism; D008954:Models, Biological; D009154:Mutation; D059807:S Phase Cell Cycle Checkpoints / Q000235:genetics; D015398:Signal Transduction
chemical_list: D064007:Ataxia Telangiectasia Mutated Proteins; D048308:Mitogen-Activated Protein Kinase 14