Journal of Biological Physics

, Volume 27, Issue 4, pp 329–359 | Cite as

DNA Replication and Cell Cycle Progression Regulatedby Long Range Interaction between Protein Complexes bound to DNA

  • Leif Matsson


A nonstationary interaction that controlsDNA replication and the cell cycle isderived from many-body physics in achemically open T cell. The model predictsa long range force F′(ξ) =– (κ/2) ξ(1 – ξ)(2 – ξ)between thepre-replication complexes (pre-RCs) boundby the origins in DNA, ξ = ϕ/N being the relativedisplacement of pre-RCs, ϕ the number of pre-RCs, N the number of replicons to be replicated,and κ the compressibilitymodulus in the lattice of pre-RCs whichbehaves dynamically like an elasticallybraced string. Initiation of DNAreplication is induced at the thresholdϕ = N by a switch ofsign of F′'(ξ), fromattraction (–) and assembly in the G1 phase (0<ϕ<N), to repulsion (+) and partialdisassembly in the S phase (N< ϕ < 2N), withrelease of licensing factors from pre-RCs,thus explaining prevention ofre-replication. Replication is terminatedby a switch of sign of force at ϕ = 2N, from repulsion inS phase back to attraction in G2, when all primed replicons havebeen duplicated once. F′(0) = 0corresponds to a resting cell in theabsence of driving force at ϕ= 0. The model thus ensures that the DNAcontent in G2 cells is exactlytwice that of G1 cells. The switch of interaction at the R-point, at which N pre-RCs have been assembled, starts the release of Rb protein thus also explaining the shift in the Rb phosphorylation from mitogen-dependent cyclinD to mitogen-independent cyclin E.Shape,slope and scale of the response curvesderived agree well with experimental datafrom dividing T cells and polymerising MTs,the variable length of which is due to anonlinear dependence of the growthamplitude on the initial concentrations oftubulin dimers and guanosine-tri-phosphate(GTP). The model also explains the dynamic instabilityin growing MTs.

Cell cycle DNA replication cyclin kinases DNA origin recognition complex microtubules DNA duplex Rb protein p27 licensing factor origin recognition complex 


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  1. 1.
    Dutta, A. and Bell, S.P.: Initiation of DNA replication in eukaryotic cells, Annu. Rev. Cell Dev. Biol. 13 (1997), 293–332.Google Scholar
  2. 2.
    Aladjem, M.I., Rodewald, L.W., Kolman, J.L. and Wahl, G.M.: Genetic Dissection of a Mammalian Replicator in the Human β-Globin Locus, Science 281 (1998), 1005-1009.Google Scholar
  3. 3.
    Bell, S.P. and Stillman, B.: ATP-Dependent Recognition of Eukaryotic Origins of DNA Replication by a Multiprotein Complex, Nature 357 (1992), 128–134.Google Scholar
  4. 4.
    Klemm, R.D., Austin, R.J. and Bell, S.P.: Coordinate Binding of ATP and Origin DNA Regulates the ATPase Activity of the Origin Recognition Complex, Cell 88 (1997), 493–502.Google Scholar
  5. 5.
    Cress, W.D. and Nevins, J.R.: Use of the E2F Transcription Factor by DNA Tumor Virus Regulatory Proteins, Curr. Topics Microbiol. Immunol 208 (1996), 63–78.Google Scholar
  6. 6.
    Sherr, C.J.: The Pezcoller Lectur: Cancer Cell Cycles Revisited, Cancer Research 60, July 15 (2000), 3689–3695.Google Scholar
  7. 7.
    Turner, J.M.: IL-2-Dependent Induction of g1 Cyclins in Primary T Cells is not Blocked by Rapamycin or Cyclosporin A, Int. Immunol. 5 (1993), 1199–1209.Google Scholar
  8. 8.
    Nourse, J., Firpo, E., Flanagan, W.M., Coats, S., Polyak, K., Lee Mong-Hong, Massague, J., Crabtree, G.R. and Roberts, J.M.: Interleukin-2-Mediated Elimination of the p27Kip1 Cyclin-Dependent Kinase Inhibitor Prevented by Rapamycin, Nature 372 (1994), 570–573.Google Scholar
  9. 9.
    Krude, T., Jackman, M., Pines, J. and Laskey, R.A.: Cyclin/Cdk-Dependent Initiation of DNA Replication in a Human Cell-Free System, Cell. Vol. 88, January 10 (1997), 109–119.Google Scholar
  10. 10.
    Harbour, J.W. and Dean, D.C.: The Rb/E2F Pathway: Expanding Roles and Emerging Paradigms, Genes & Development 14 (2000), 2393–2409.Google Scholar
  11. 11.
    Zou Lee and Stillman, B.: Formation of a Preinitiation Complex by S-phase Cyclin CDK-Dependendent Loading of Cdc45p onto Chromatin, Science 280 (1998), 593–596.Google Scholar
  12. 12.
    Smith, K.A.: Why do Cells Count?’ In: Matsson, L. (ed.), Nonlinear Cooperative Phenomena in Biological Systems, World Scientific, Singapore, 1998, pp. 13–19.Google Scholar
  13. 13.
    Voter, W.A. and Erickson, H.P.: The Kinetics of Microtubule Assembly, J. Biol. Chem. 259 (1984), 10430–10438.Google Scholar
  14. 14.
    Mitchison, T. and Kirschner, M.: Dynamic Instability of Microtubule Growth, Nature (London) 312 (1984), 237–242.Google Scholar
  15. 15.
    Smith, K.A.: The Interleukin-2 Receptor, Annu. Rev. Cell Biol. 5 (1989), 397–425.Google Scholar
  16. 16.
    Collings, P.J.: Liquid Crystals: Nature's Delicate Phase of Matter, Adam Hilger, Bristol UK, 1990, pp. 147–216.Google Scholar
  17. 17.
    Hill, A.V.: The Combinations of Hemoglobin with Oxygen and with Carbon Monoxide I, Biochem. J. 7 (1913), 471–480.Google Scholar
  18. 18.
    Langmuir, I.: The Adsorption of Gases on Plane Surfaces of Glass, Mica and Platinum, J. Am. Chem. Soc. 40 (1918), 1361–1403.Google Scholar
  19. 19.
    Bevan, J.A., Oriowo, M.A. and Bevan, R.D.: Physiological Variation in α-Adrenoceptor-Mediated Arterial Sensitivity: Relation to Agonist Affinity, Science 234 (1986), 196–197.Google Scholar
  20. 20.
    Barlow, R. and Blake, J.F.: Hill Coefficients and the Logistic Equation, Trends Pharmacol. Sci. 10 (1989), 440–441.Google Scholar
  21. 21.
    Bevan, J.A., Bevan, R.D., Kite, K. and Oriowo, M.A.: Species Differences in Sensitivity of Aortae to Norepinephrine are Related to α-Adrenoceptor Affinity, Trends Pharmacol. Sci. 9 (1988), 87–89.Google Scholar
  22. 22.
    Cantrell, D.A. and Smith, K.A.: The Interleukin-2 T-Cell System: A New Cell Growth Model, Science 224 (1984), 1312–1316.Google Scholar
  23. 23.
    Viola, A. and Lanzavecchia, A.: T Cell Activation Determined by T Cell Receptor Number and Tunable Thresholds, Science 273 (1996), 104–106.Google Scholar
  24. 24.
    Rothenberg, E.V.: How T Cells Count, Science 273 (1996), 78–79.Google Scholar
  25. 25.
    Smith, K.A.: T-cell growth factor and glucocorticoids: Opposing regulatory hormones in neoplastic T-cell growth, Immunobiology. 161 (1982), 157–173.Google Scholar
  26. 26.
    Paton, W.D.M.: A Theory of Drug Action Based on the Rate of Drug-Receptor Combination, Proc. R. Soc. London Ser.B, 154 (1961), 21–69.Google Scholar
  27. 27.
    Matsson, L.: Response Theory for Non-Stationary Ligand-Receptor Interaction and a Solution to the Growth Signal Firing Problem, J. Theor. Biol. 180 (1996), 93–104.Google Scholar
  28. 28.
    Matsson, L.: Long Range Interaction between Protein Complexes in DNA Controls Replication and Cell Cycle Progression, J. Biol. Syst. 9 No.1 (2001), 41–65. (On page 52, 4:th line above (5.1) in this reference work, the upper limit of the interval should be N, not 5.)Google Scholar
  29. 29.
    Ferell, J.E. and Machleder, E.M.: The Biochemical Basis of an All-or-None Cell Fate Switch in Xenopus Oocytes, Science 280 (1998), 895–898.Google Scholar
  30. 30.
    Koshland Jr., D.E.: The Era of Pathway Quantification, Science 273 (1998), 852–853.Google Scholar
  31. 31.
    Rajaraman, R.: Solitons and Instantons, North Holland, Amsterdam, 1982, pp. 1–83.Google Scholar
  32. 32.
    Ziman, J.M.: Principles of the theory of solids, Cambridge University Press, Cambridge, 1964, pp. 324–346.Google Scholar
  33. 33.
    Mitchison, T. and Kirschner, M.: Microtubule Assembly Nucleated by Isolated Centrosomes, Nature (London) 312 (1984), 232–237.Google Scholar
  34. 34.
    Nguyen, V.Q., Co, C. and Li, J.J.: Cyclin-Dependent Kinases Prevent DNA Replication through Multiple Mechanisms, Nature 411 (2001), 1068–1073.Google Scholar
  35. 35.
    Davenport, R.J.: DNA: Once Copied, Thrice Blocked, Science 292 (2001), 2415–2417.Google Scholar
  36. 36.
    Morse, P. and Feshbach, H.: Methods of Mathematical Physics Part I, McGraw-Hill, New-York, 1953, pp. 139, 256, 305, 729–736.Google Scholar
  37. 37.
    Ingber, D.: Cellular Tensegrity, Defining New Rules of Biological Design that Govern the Cytoskeleton, J. Cell. Sci. 104 (1993), 613–627.Google Scholar
  38. 38.
    Fröhlich, H.: Theoretical Physics and Biology, In: H. Fröhlich (ed.), Biological Coherence and Response to external Stimuli, Springer Verlag, Berlin, 1988, pp. 1–24.Google Scholar
  39. 39.
    Sherr, C.J. and Roberts, J.M.: CDK Inhibitors: Positive and Negative Regulators of G1-Phase Progression, Genes & Development 13 (1999), 1501–1512.Google Scholar
  40. 40.
    Michaelis, L. and Menten, M.L.: Die Kinetik der Invertinwirkung, Biochem. Z. 49 (1913) 333–369.Google Scholar
  41. 41.
    Huberman, J.A.: Choosing a Place to Begin, Science 281 (1998), 929–930.Google Scholar
  42. 42.
    Pennisi, E.: Science 283 (1999), 770–771.Google Scholar
  43. 43.
    Hinchcliffe, E.H., Li Chuan, Thompson, E.A., Maller, J.L. and Sluder, G.: Requirement of Cdk2-Cyclin E Activity for Repeated centrosome Reproduction in Xenopus Egg Extracts, Science 283 (1999), 851–854.Google Scholar
  44. 44.
    Melki, R., Carlier, M.-F., Pantaloni, D. and Timasheff, S.N.: Cold Depolymerization of Microtubules to Double Rings: Geometric Stabilization of Assemblies, Biochemistry 28 (1989), 9143–9152.Google Scholar
  45. 45.
    Matsson, L.: DNA and Microtubules as Vortex-Strings in Superconductor-like Dynamics, In: Frauenfelder, H., Matsson, L. and Sayakanit, V. (eds.), First Workshop on Biological Physics 2000, 18-22 Sept. 2000, Chulalongkorn University, Bangkok, Thailand. World Scientific, Singapore, 2001.Google Scholar

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© Kluwer Academic Publishers 2001

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  • Leif Matsson

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