Deciphering p53 dynamics and cell fate in DNA damage response using mathematical modeling
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Deciphering p53 dynamics and cell fate in DNA damage response using mathematical modeling Nanfei Yang1 · Tingzhe Sun2 · Pingping Shen1 Received: 31 May 2020 / Revised: 1 July 2020 / Accepted: 11 July 2020 © Shenzhen University School of Medicine; Fondazione Istituto FIRC di Oncologia Molecolare 2020
Abstract The tumor suppressor p53 is activated in response to cellular stresses. The transcription factor p53 can activate the expression of numerous genes leading to cell cycle arrest, senescence or apoptosis. The p53 network exhibits complex stimulusdependent dynamics under stressed and non-stressed conditions. Mathematical models contribute significantly to enhanced understanding of p53 network topology. In this review, we discuss the evolution of kinetic p53 modeling, multiple mechanisms for distinct p53 dynamics, and how the temporal p53 dynamics determine cell fate over the last 2 decades. The Information encoding and decoding strategies through p53 signaling network enable cells to undergo appropriate cellular outcomes. Keywords p53 · Mathematical model · Feedback loop · Cell fate decision
Introduction The mammalian cells are constantly confronted with intrinsic stress (Lowndes 2001). Genomic rearrangement and replication may result in DNA lesions (So et al. 2017). Cellular metabolism can generate reactive oxygen species to extensively attack biomolecules (Kultz 2005). Environmental stressors such as irradiation also jeopardize the integrity of genome. The multicellular organism should initiate a program to halt cell division and prevent propagation of mutations in the event of excessive DNA damage. The DNA damage will initiate a signaling cascade known as DNA damage response (DDR) (Shikazono et al. 2009). The DDR may promote DNA repair and limit normal cell cycle progression until damages are fully resolved. The critical role of DDR is highlighted by the identification of various cancer-associated * Tingzhe Sun [email protected] * Pingping Shen [email protected] 1
State Key Laboratory of Pharmaceutical Biotechnology and The Comprehensive Cancer Center, Nanjing Drum Tower Hospital, MOE Key Laboratory of Model Animal for Disease Study, School of Life Sciences, Nanjing University, Nanjing 210046, China
School of Life Sciences, Anqing Normal University, North Jixian Road, No. 1318, Anqing 246133, Anhui, China
2
genes within DNA repair signaling (Krenning et al. 2019). A notable mediator in DDR is the ‘guardian of the genome’ p53 and TP53 loss usually leads to defects in DNA repair and cancer predisposition (Tang et al. 2020; Lane 1992). The DNA double strand breaks (DSBs), which are classified as the clustered type of severe DNA lesions, can induce rapid trans-autophosphorylation of ataxia-telangiectasia mutated protein (ATM) (Bakkenist and Kastan 2003), which then phosphorylates p53 along with other substrates (Banin et al. 1998). ATM-mediated p53 phosphorylation activates p53 and initiates a series of tightly controlled downstream responses (Fig. 1a). The ultraviolet (UV) light, h
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