Modelling the onset of senescence at the G1-S cell cycle checkpointReport as inadecuate




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BMC Genomics

, 15:S7

First Online: 27 October 2014DOI: 10.1186-1471-2164-15-S7-S7

Cite this article as: Mombach, J.C., Bugs, C.A. & Chaouiya, C. BMC Genomics 2014 15Suppl 7: S7. doi:10.1186-1471-2164-15-S7-S7

Abstract

BackgroundDNA 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.

ResultsWe 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.

ConclusionsAs 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.

KeywordsSignalling network Logical modelling Senescence DNA-damage Cell fate Cell cycle checkpoint Electronic supplementary materialThe online version of this article doi:10.1186-1471-2164-15-S7-S7 contains supplementary material, which is available to authorized users.

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Author: José CM Mombach - Cristhian A Bugs - Claudine Chaouiya

Source: https://link.springer.com/



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