title: A switch-like dynamic mechanism for the initiation of replicative senescence.
abstract: Telomeres are specialized structures protecting chromosomes against genome instability. Telomeres shorten with cell division, and replicative senescence is induced when telomeres are badly eroded. Whereas TRF2 (telomeric-repeat binding factor 2), ATM (ataxia telangiectasia mutated) and p53 have been identified involved in senescence induction, how it is triggered remains unclear. Here, we propose an integrated model associating telomere loss with senescence trigger. We characterize the dynamics of telomere shorting and the p53-centered regulatory network. We show that senescence is initiated in a switch-like manner when both the shortest telomere becomes uncapped and the TRF2-ATM-p53-Siah1 positive feedback loop is switched on. This work provides a coherent picture of senescence induction in terms of telomere shortening and p53 activation.
authors.affiliation: National Laboratory of Solid State Microstructures and Department of Physics, Nanjing University, Nanjing 210093, China.
authors.forename: Qing-He
authors.initials: QH
authors.lastname: Zhang
authors.affiliation: National Laboratory of Solid State Microstructures and Department of Physics, Nanjing University, Nanjing 210093, China.
authors.forename: Xiao-Jun
authors.initials: XJ
authors.lastname: Tian
authors.affiliation: National Laboratory of Solid State Microstructures and Department of Physics, Nanjing University, Nanjing 210093, China. Electronic address: fliu@nju.edu.cn.
authors.forename: Feng
authors.initials: F
authors.lastname: Liu
authors.affiliation: National Laboratory of Solid State Microstructures and Department of Physics, Nanjing University, Nanjing 210093, China. Electronic address: wangwei@nju.edu.cn.
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
mesh_terms: D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism; D004171:Diploidy; D015536:Down-Regulation; D025461:Feedback, Physiological; D005347:Fibroblasts / Q000166:cytology; D006801:Humans; D008954:Models, Biological; D009687:Nuclear Proteins / Q000378:metabolism; D010766:Phosphorylation; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D059506:Telomere Shortening; D035341:Telomeric Repeat Binding Protein 2 / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D000098563:Seven in Absentia Proteins
chemical_list: D009687:Nuclear Proteins; D035341:Telomeric Repeat Binding Protein 2; D016159:Tumor Suppressor Protein p53; D051736:Proto-Oncogene Proteins c-mdm2; D044767:Ubiquitin-Protein Ligases; D000098563:Seven in Absentia Proteins; D064007:Ataxia Telangiectasia Mutated Proteins
keywords: Bistable switch; Regulatory network; Replicative senescence; Telomere shortening; p53 activation