A Mathematical Model for the Detection Mechanism of DNA Double-strand Breaks Depending on Autophosphorylation of ATM

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2009 Apr 15

PMID 19365581

Citations 13

Authors

Kazunari Mouri

Jose C Nacher

Tatsuya Akutsu

Affiliations

Soon will be listed here.

Abstract

Background: After IR stress, DNA double-strand breaks (DSBs) occur and repair proteins (RPs) bind to them, generating DSB-RP complexes (DSBCs), which results in repaired DSBs (RDSBs). In recent experimental studies, it is suggested that the ATM proteins detect these DNA lesions depending on the autophosphorylation of ATM which exists as a dimer before phosphorylation. Interestingly, the ATM proteins can work as a sensor for a small number of DSBs (approximately 18 DSBs in a cell after exposure to IR). Thus the ATM proteins amplify the small input signals based on the phosphorylation of the ATM dimer proteins. The true DSB-detection mechanism depending on ATM autophosphorylation has yet to be clarified.

Methodology/principal Findings: We propose a mathematical model for the detection mechanism of DSBs by ATM. Our model includes both a DSB-repair mechanism and an ATM-phosphorylation mechanism. We model the former mechanism as a stochastic process, and obtain theoretical mean values of DSBs and DSBCs. In the latter mechanism, it is known that ATM autophosphorylates itself, and we find that the autophosphorylation induces bifurcation of the phosphorylated ATM (ATM*). The bifurcation diagram depends on the total concentration of ATM, which makes three types of steady state diagrams of ATM*: monostable, reversible bistable, and irreversible bistable. Bistability exists depending on the Hill coefficient in the equation of ATM autophosphorylation, and it emerges as the total concentration of ATM increases. Combining these two mechanisms, we find that ATM* exhibits switch-like behaviour in the presence of bistability, and the detection time after DNA damage decreases when the total concentration of ATM increases.

Conclusions/significance: This work provides a mathematical model that explains the DSB-detection mechanism depending on ATM autophosphorylation. These results indicate that positive auto-regulation works both as a sensor and amplifier of small input signals.

Citing Articles

Two-dimensional polynomial type canonical relaxation oscillator model for p53 dynamics.

Demirkiran G, Kalayci Demir G, Guzelis C IET Syst Biol. 2021; 12(4):138-147.

PMID: 33451182 PMC: 8687216. DOI: 10.1049/iet-syb.2017.0077.

Mathematical Model of ATM Activation and Chromatin Relaxation by Ionizing Radiation.

Li Y, Cucinotta F Int J Mol Sci. 2020; 21(4).

PMID: 32059363 PMC: 7072770. DOI: 10.3390/ijms21041214.

Roles of cellular heterogeneity, intrinsic and extrinsic noise in variability of p53 oscillation.

Wang D, Wang S, Huang B, Liu F Sci Rep. 2019; 9(1):5883.

PMID: 30971810 PMC: 6458166. DOI: 10.1038/s41598-019-41904-9.

Recent progress and open challenges in modeling p53 dynamics in single cells.

Batchelor E, Loewer A Curr Opin Syst Biol. 2017; 3:54-59.

PMID: 29062976 PMC: 5650191. DOI: 10.1016/j.coisb.2017.04.007.

The Life Span Model of Suicide and Its Neurobiological Foundation.

Ludwig B, Roy B, Wang Q, Birur B, Dwivedi Y Front Neurosci. 2017; 11:74.

PMID: 28261051 PMC: 5306400. DOI: 10.3389/fnins.2017.00074.

References

Samuni A, DeGraff W, Krishna M, Mitchell J . Cellular sites of H2O2-induced damage and their protection by nitroxides. Biochim Biophys Acta. 2001; 1525(1-2):70-6. DOI: 10.1016/s0304-4165(00)00172-0. View

Xiong W, Ferrell Jr J . A positive-feedback-based bistable 'memory module' that governs a cell fate decision. Nature. 2003; 426(6965):460-5. DOI: 10.1038/nature02089. View

Kiehl T, Mattheyses R, Simmons M . Hybrid simulation of cellular behavior. Bioinformatics. 2004; 20(3):316-22. DOI: 10.1093/bioinformatics/btg409. View

Bakkenist C, Kastan M . DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation. Nature. 2003; 421(6922):499-506. DOI: 10.1038/nature01368. View

Ozbudak E, Thattai M, Lim H, Shraiman B, van Oudenaarden A . Multistability in the lactose utilization network of Escherichia coli. Nature. 2004; 427(6976):737-40. DOI: 10.1038/nature02298. View

Becskei A, Seraphin B, Serrano L . Positive feedback in eukaryotic gene networks: cell differentiation by graded to binary response conversion. EMBO J. 2001; 20(10):2528-35. PMC: 125456. DOI: 10.1093/emboj/20.10.2528. View

GARDNER T, Cantor C, Collins J . Construction of a genetic toggle switch in Escherichia coli. Nature. 2000; 403(6767):339-42. DOI: 10.1038/35002131. View

Arkin A, Ross J, McAdams H . Stochastic kinetic analysis of developmental pathway bifurcation in phage lambda-infected Escherichia coli cells. Genetics. 1998; 149(4):1633-48. PMC: 1460268. DOI: 10.1093/genetics/149.4.1633. View

Nair V, Yuen T, Olanow C, Sealfon S . Early single cell bifurcation of pro- and antiapoptotic states during oxidative stress. J Biol Chem. 2004; 279(26):27494-501. DOI: 10.1074/jbc.M312135200. View

10.

Ferrell Jr J, Machleder E . The biochemical basis of an all-or-none cell fate switch in Xenopus oocytes. Science. 1998; 280(5365):895-8. DOI: 10.1126/science.280.5365.895. View

11.

Maya R, Segel L, Alon U, Levine A, Oren M . Generation of oscillations by the p53-Mdm2 feedback loop: a theoretical and experimental study. Proc Natl Acad Sci U S A. 2000; 97(21):11250-5. PMC: 17186. DOI: 10.1073/pnas.210171597. View

12.

Lahav G, Rosenfeld N, Sigal A, Geva-Zatorsky N, Levine A, Elowitz M . Dynamics of the p53-Mdm2 feedback loop in individual cells. Nat Genet. 2004; 36(2):147-50. DOI: 10.1038/ng1293. View

13.

Isaacs F, Hasty J, Cantor C, Collins J . Prediction and measurement of an autoregulatory genetic module. Proc Natl Acad Sci U S A. 2003; 100(13):7714-9. PMC: 164653. DOI: 10.1073/pnas.1332628100. View

14.

Kastan M, Lim D . The many substrates and functions of ATM. Nat Rev Mol Cell Biol. 2001; 1(3):179-86. DOI: 10.1038/35043058. View

15.

Lee J, Paull T . Direct activation of the ATM protein kinase by the Mre11/Rad50/Nbs1 complex. Science. 2004; 304(5667):93-6. DOI: 10.1126/science.1091496. View

16.

You Z, Bailis J, Johnson S, Dilworth S, Hunter T . Rapid activation of ATM on DNA flanking double-strand breaks. Nat Cell Biol. 2007; 9(11):1311-8. DOI: 10.1038/ncb1651. View

17.

Batchelor E, Mock C, Bhan I, Loewer A, Lahav G . Recurrent initiation: a mechanism for triggering p53 pulses in response to DNA damage. Mol Cell. 2008; 30(3):277-89. PMC: 2579769. DOI: 10.1016/j.molcel.2008.03.016. View

18.

Mello Filho A, Meneghini R . In vivo formation of single-strand breaks in DNA by hydrogen peroxide is mediated by the Haber-Weiss reaction. Biochim Biophys Acta. 1984; 781(1-2):56-63. DOI: 10.1016/0167-4781(84)90123-4. View

19.

Rao C, Wolf D, Arkin A . Control, exploitation and tolerance of intracellular noise. Nature. 2002; 420(6912):231-7. DOI: 10.1038/nature01258. View

20.

Elowitz M, Levine A, Siggia E, Swain P . Stochastic gene expression in a single cell. Science. 2002; 297(5584):1183-6. DOI: 10.1126/science.1070919. View