Research Papers:

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

Tingzhe Sun _, Xinda Li and Pingping Shen

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Oncotarget. 2017; 8:17105-17114. https://doi.org/10.18632/oncotarget.15062

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Tingzhe Sun1,*, Xinda Li2,*, Pingping Shen2

1School of Life Sciences, AnQing Normal University, AnQing, Anhui, 246011, China

2State 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: [email protected]

Pingping Shen, email: [email protected]

Keywords: amplified p53 pulse, DNA-PK inhibitor, cell fate, mutual information, robustness

Received: October 19, 2016     Accepted: January 10, 2017     Published: February 03, 2017


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.

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