To senesce or not to senesce: how primary human fibroblasts decide their cell fate after DNA damage

Aging
Gabriel KollarovicJörg Schaber

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 sensitiz...Continue Reading

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Citations

Apr 22, 2017·Oncotarget·Maja Studencka, Jörg Schaber
Apr 17, 2020·Biology of Sex Differences·Joshua B RubinJingqin Luo
May 19, 2017·Frontiers in Immunology·Franz RödelStephanie Hehlgans

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Datasets Mentioned

BETA
GM
MODEL1505080000

Methods Mentioned

BETA
FACS
irradiating
protein assay
electrophoresis
flow cytometry
transfection
transfections

Software Mentioned

Flowing
COPASI
Image Studio Lite
MC sim

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