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.
Highlights
Faithful repair of DNA damage is critically important for genomic integrity
Sensing DNA double strand breaks is facilitated by phosphatidylinositol 3-kinase (PI3K)-like kinase (PIKK) family members including ataxia telangiectasia-mutated ATR (ATM), ATR, and DNA-dependent protein kinase full-width at halfmaximum (FWHM) (DNA-PK) (DNA-dependent protein kinase)
After DNA-PK inhibition, we found that the first p53 pulse was substantially amplified in both duration and amplitude (Figure 1B)
Summary
Faithful repair of DNA damage is critically important for genomic integrity. Cells have evolved multiple strategies to cope with DNA damage by inducing cell cycle arrest, senescence or apoptosis [1]. One of the most detrimental DNA damages is DNA double strand breaks (DSBs). Defect in DNA damage response (DDR) may favor a tumor-prone phenotype [2]. The link between dysfunctional DDR and tumor development defines the importance of DNA damage repair. Sensing DNA double strand breaks is facilitated by phosphatidylinositol 3-kinase (PI3K)-like kinase (PIKK) family members including ATM (ataxia telangiectasiamutated), ATR (ataxia telangiectasia and Rad3-related protein), and DNA-PK (DNA-dependent protein kinase). The kinetic modifications of PIKK members may dictate DSB repair pathway choice [3]. ATM primarily responds to DNA double strand breaks while recent findings have implied that ATR is involved in DSB repair by activating end processing [4]. The activation of PIKK kinases may relay signals to tumor suppressor p53 [5]
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