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Exploring the Influence of Parameters on the p53 Response When Single-Stranded Breaks and Double-Stranded Breaks Coexist

  • Aiqing Ma
  • Xianhua DaiEmail author
Original research article

Abstract

The p53 response to DNA damage is closely related to cell fate decisions. P53 preferentially responds to single-stranded breaks (SSBs) exhibiting a graded response when single-stranded breaks (SSBs) and double-stranded breaks (DSBs) coexist. However, how p53 natural preferential response is affected by kinetic parameters remains to be elucidated. Here, based on the hybrid model I, we computationally searched all the parameters and parameter combinations in the parameter space to identify those that could alter the natural preferential response of p53 when SSBs and DSBs coexist. Firstly, when a single parameter is changed, the parameters that can alter graded response to produce p53 pulse response are production rate of ATM- and Rad3-related kinase(ATR) (beta2), ATR degradation rate (alf2) and ATR-dependent p53 production rate (beta31). Secondly, when double parameters are changed, the combinations of beta2/alf2/beta31 and any other parameters are capable of altering the p53 natural preferential response, and the combination of ataxia-telangiectasia mutated kinase (ATM)-dependent p53 production rate (beta3) and Wip1-dependent p53 degradation rate (alf35) is also capable of altering the p53 natural preferential response. Thirdly, we analyzed the sensitivity of both pulse amplitude and apoptosis to kinetic parameters. We find that pulse amplitude is most sensitive to ATM-dependent p53 production rate (beta3), and apoptosis is more sensitive to damage-dependent ATM production rate (beta1), wip1-dependent ATM degradation rate (alf15), wip1 production rate (beta5) and wip1 degradation rate (alf5). What is more, the smaller the value of alf15/beta5 or the larger the value of beta1/alf5, the more susceptible the cells are to apoptosis. These results provide clues to design more effective and less toxic targeted treatments for cancer.

Keywords

Single-stranded breaks (SSBs) Double-stranded breaks (DSBs) P53 response Apoptosis Parameter sensitivity analysis 

Notes

Acknowledgements

Aiqing Ma and X. H. Dai designed and implemented the study. Aiqing Ma accomplished the numerical analysis. Aiqing Ma also analyzed the results and drafted the manuscript. All of them participated in the discussion and approved the final manuscript.

Funding

This work was supported by the National Natural Science Foundation of China (Grant no. 61872396).

Compliance with Ethical Standards

Conflict of Interest

The authors declare that there is no conflict of interests regarding the publication of this paper.

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Copyright information

© International Association of Scientists in the Interdisciplinary Areas 2019

Authors and Affiliations

  1. 1.School of Electronics and Information TechnologySun Yat-Sen UniversityGuangzhouChina

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