Modeling amplified p53 responses under DNA-PK inhibition in DNA damage response

// Tingzhe Sun 1, * , Xinda Li 2, * , Pingping Shen 2 1 School of Life Sciences, AnQing Normal University, AnQing, Anhui, 246011, China 2 State Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Nanjing, 210023, China * These authors share the first authorship Correspondence to: Tingzhe Sun, email: confucian007@126.com Pingping Shen, email: ppshen@nju.edu.cn Keywords: amplified p53 pulse, DNA-PK inhibitor, cell fate, mutual information, robustness Received: October 19, 2016      Accepted: January 10, 2017      Published: February 03, 2017 ABSTRACT During DNA double strand breaks (DSBs) repair, coordinated activation of phosphatidylinositol 3-kinase (PI3K)-like kinases can activate p53 signaling pathway. Recent findings have identified novel interplays among these kinases demonstrating amplified first p53 pulses under DNA-PK inhibition. However, no theoretical model has been developed to characterize such dynamics. In current work, we modeled the prolonged p53 pulses with DNA-PK inhibitor. We could identify a dose-dependent increase in the first pulse amplitude and width. Meanwhile, weakened DNA-PK mediated ATM inhibition was insufficient to reproduce such dynamic behavior. Moreover, the information flow was shifted predominantly to the first pulse under DNA-PK inhibition. Furthermore, the amplified p53 responses were relatively robust. Taken together, our model can faithfully replicate amplified p53 responses under DNA-PK inhibition and provide insights into cell fate decision by manipulating p53 dynamics.