title: To senesce or not to senesce: how primary human fibroblasts decide their cell fate after DNA damage.
abstract: Excessive DNA damage can induce an irreversible cell cycle arrest, called senescence, which is generally perceived as an important tumour-suppressor mechanism. However, it is unclear how cells decide whether to senesce or not after DNA damage. By combining experimental data with a parameterized mathematical model we elucidate this cell fate decision at the G1-S transition. Our model provides a quantitative and conceptually new understanding of how human fibroblasts decide whether DNA damage is beyond repair and senesce. Model and data imply that the G1-S transition is regulated by a bistable hysteresis switch with respect to Cdk2 activity, which in turn is controlled by the Cdk2/p21 ratio rather than cyclin abundance. We experimentally confirm the resulting predictions that to induce senescence i) in healthy cells both high initial and elevated background DNA damage are necessary and sufficient, and ii) in already damaged cells much lower additional DNA damage is sufficient. Our study provides a mechanistic explanation of a) how noise in protein abundances allows cells to overcome the G1-S arrest even with substantial DNA damage, potentially leading to neoplasia, and b) how accumulating DNA damage with age increasingly sensitizes cells for senescence.
authors.affiliation: Institute for Experimental Internal Medicine, Medical Faculty, Otto-von-Guericke University, Magdeburg, Germany.|Cancer Research Institute, Slovak Academy of Sciences, Bratislava, Slovakia.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Kollarovic
authors.affiliation: Institute for Experimental Internal Medicine, Medical Faculty, Otto-von-Guericke University, Magdeburg, Germany.
authors.forename: Maja
authors.initials: M
authors.lastname: Studencka
authors.affiliation: Institute for Experimental Internal Medicine, Medical Faculty, Otto-von-Guericke University, Magdeburg, Germany.
authors.forename: Lyubomira
authors.initials: L
authors.lastname: Ivanova
authors.affiliation: Institute for Experimental Internal Medicine, Medical Faculty, Otto-von-Guericke University, Magdeburg, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Lauenstein
authors.affiliation: Institute for Experimental Internal Medicine, Medical Faculty, Otto-von-Guericke University, Magdeburg, Germany.
authors.forename: Kristina
authors.initials: K
authors.lastname: Heinze
authors.affiliation: Institute for Experimental Internal Medicine, Medical Faculty, Otto-von-Guericke University, Magdeburg, Germany.
authors.forename: Anastasiya
authors.initials: A
authors.lastname: Lapytsko
authors.affiliation: Institute for Experimental Internal Medicine, Medical Faculty, Otto-von-Guericke University, Magdeburg, Germany.
authors.forename: Soheil Rastgou
authors.initials: SR
authors.lastname: Talemi
authors.affiliation: Institute for Experimental Internal Medicine, Medical Faculty, Otto-von-Guericke University, Magdeburg, Germany.
authors.forename: Ana Sofia
authors.initials: AS
authors.lastname: Figueiredo
authors.affiliation: Institute for Experimental Internal Medicine, Medical Faculty, Otto-von-Guericke University, Magdeburg, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Schaber
mesh_terms: D049109:Cell Proliferation / Q000528:radiation effects; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000528:radiation effects; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage; D004307:Dose-Response Relationship, Radiation; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology* / Q000528:radiation effects; D059585:G1 Phase Cell Cycle Checkpoints; D006801:Humans; D008954:Models, Biological; D061251:Primary Cell Culture; D034622:RNA Interference; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection
chemical_list: C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2
keywords: Cdk2/p21 ratio; G1-S transition; bistable hysteresis switch; cumulative DNA damage; dynamic model
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