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Do Femtonewton Forces Affect Genetic Function? A Review

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Abstract

Protein-Mediated DNA looping is intricately related to gene expression. Therefore any mechanical constraint that disrupts loop formation can play a significant role in gene regulation. Polymer physics models predict that less than a piconewton of force may be sufficient to prevent the formation of DNA loops. Thus, it appears that tension can act as a molecular switch that controls the much larger forces associated with the processive motion of RNA polymerase. Since RNAP can exert forces over 20 pN before it stalls, a ‘substrate tension switch’ could offer a force advantage of two orders of magnitude. Evidence for such a mechanism is seen in recent in vitro micromanipulation experiments. In this article we provide new perspective on existing theory and experimental data on DNA looping in vitro and in vivo. We elaborate on the connection between tension and a variety of other intracellular mechanical constraints including sequence specific curvature and supercoiling. In the process, we emphasize that the richness and versatility of DNA mechanics opens up a whole new paradigm of gene regulation to explore.

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Abbreviations

WLC:

Wormlike Chain

SM:

Sankararaman and Marko Model

BTM:

Blumberg, Tkachenko and Meiners Model

SY:

Shimada and Yamakawa Model

References

  1. Duncan, R.L. and C.H. Turner.: Mechanotransduction and the Functional-Response of Bone to Mechanical Strain. Calcified Tissue International 57 (1995), 344–358.

    Article  PubMed  Google Scholar 

  2. Liu, M.Y., A.K. Tanswell and M. Post.: Mechanical force-induced signal transduction in lung cells. Am. J. Physiol.-Lung Cell. Mol. Physiol. 277 (1999), L667–L683.

    Google Scholar 

  3. Ingber, D.E.: Tensegrity: The architectural basis of cellular mechanotransduction. Annu. Rev. Physiol. 59 (1997), 575–599.

    Article  PubMed  Google Scholar 

  4. Ingber, D.E.: Mechanobiology and diseases of mechanotransduction. Annals of Medicine 35 (2003), 564–577.

    Article  PubMed  Google Scholar 

  5. Ingber, D.E.: Mechanical signalling and the cellular response to extracellular matrix in angiogenesis and cardiovascular physiology. Circulation Research 91 (2002), 877–887.

    Article  PubMed  Google Scholar 

  6. Knoll, R., M. Hoshijima and K. Chien.: Cardiac mechanotransduction and implications for heart disease. Journal of Molecular Medicine-Jmm 81 (2003), 750–756.

    Article  Google Scholar 

  7. Paszek, M.J. and V.M. Weaver.: The tension mounts: Mechanics meets morphogenesis and malignancy. Journal of Mammary Gland Biology and Neoplasia 9 (2004), 325–342.

    Article  PubMed  Google Scholar 

  8. Martinac, B.: Mechanosensitive ion channels: molecules of mechanotransduction. Journal of Cell Science 117 (2004), 2449–2460.

    Article  PubMed  Google Scholar 

  9. Maniotis, A.J., C.S. Chen and D.E. Ingber.: Demonstration of mechanical connections between integrins cytoskeletal filaments, and nucleoplasm that stabilize nuclear structure. Proc. Natl. Acad. Sci. U.S.A. 94 (1997), 849–854.

    Article  PubMed  ADS  Google Scholar 

  10. Bensimon, D.: Force: a new structural control parameter? Structure 4 (1996), 885–889.

    Article  PubMed  Google Scholar 

  11. Cocco, S., J.F. Marko and R. Monasson.: Theoretical models for single-molecule DNA and RNA experiments: From elasticity to unzipping. Comptes Rendus Physique 3 (2002), 569–584.

    Article  ADS  Google Scholar 

  12. Wang, M.D., M.J. Schnitzer, H. Yin, R. Landick, J. Gelles and S.M. Block.: Force and velocity measured for single molecules of RNA polymerase. Science 282 (1998), 902–907.

    Article  PubMed  ADS  Google Scholar 

  13. Brower-Toland, B.D., C.L. Smith, R.C. Yeh, J.T. Lis, C.L. Peterson and M.D. Wang.: Mechanical disruption of individual nucleosomes reveals a reversible multistage release of DNA. Proc. Natl. Acad. Sci. U.S.A. 99 (2002), 1960–1965.

    Article  PubMed  ADS  Google Scholar 

  14. Bustamante, C., Y.R. Chemla, N.R. Forde and D. Izhaky.: Mechanical processes in biochemistry. Annual Review of Biochemistry 73 (2004), 705–748.

    Article  PubMed  Google Scholar 

  15. Bustamante, C., J.F. Marko, E.D. Siggia and S. Smith.: Entropic elasticity of lambda-phage DNA. Science 265 (1994), 1599–1600.

    Article  PubMed  ADS  Google Scholar 

  16. Schleif, R.: DNA Looping. Annual Review of Biochemistry 61 (1992), 199–223.

    Article  PubMed  Google Scholar 

  17. Ptashne, M. and A. Gann.: Genes and Signals. Cold Spring Harbor, N.Y.: Cold Spring Harbor Laboratory Press. 192 (2002).

  18. Droge, P. and B. Muller-Hill.: High local protein concentrations at promoters: strategies in prokaryotic and eukaryotic cells. Bioessays 23 (2001), 179–183.

    Article  PubMed  Google Scholar 

  19. Marko, J.F. and E.D. Siggia.: Stretching DNA. Macromolecules 28 (1995), 8759–8770.

    Article  Google Scholar 

  20. Smith, S.B., L. Finzi and C. Bustamante.: Direct Mechanical Measurements of the Elasticity of Single DNA-Molecules by Using Magnetic Beads. Science 258 (1992), 1122–1126.

    Article  PubMed  ADS  Google Scholar 

  21. Meiners, J.C. and S.R. Quake.: Femtonewton force spectroscopy of single extended DNA molecules. Physical Review Letters 84 (2000), 5014–5017.

    Article  PubMed  ADS  Google Scholar 

  22. Marko, J.F. and E.D. Siggia.: Driving proteins off DNA using applied tension. Biophysical Journal 73 (1997), 2173–2178.

    PubMed  Google Scholar 

  23. Sankararaman, S. and J.F. Marko.: Formation of loops in DNA under tension. Physical Review E (Statistical, Nonlinear, and Soft Matter Physics) 71 (2005), 021911.

    Google Scholar 

  24. Blumberg, S., A.V. Tkachenko and J.-C. Meiners.: Disruption of Protein-Mediated DNA Looping by Tension in the Substrate DNA. Biophys. J. 88 (2005), 1692–1701.

    Article  PubMed  Google Scholar 

  25. Kratky, O. and G. Porod.: Rontgenuntersuchung Geloster Fadenmolekule. Recueil Des Travaux Chimiques Des Pays-Bas-Journal of the Royal Netherlands Chemical Society 68 (1949), 1106–1122.

    Google Scholar 

  26. Yamakawa, H. and W.H. Stockmayer.: Statistical Mechanics of Wormlike Chains. II. Excluded Volume Effects. The Journal of Chemical Physics 57 (1972), 2843–2854.

    Article  ADS  Google Scholar 

  27. Cloutier, T.E. and J. Widom. Spontaneous sharp bending of double-stranded DNA. Molecular Cell 14 (2004), 355–362.

    Article  PubMed  Google Scholar 

  28. Yan, J., R. Kawamura and J.F. Marko.: Statistics of loop formation along double helix DNAs. Physical Review E (2005), 71.

  29. Rudnick, J. and R. Bruinsma.: DNA-protein cooperative binding through variable-range elastic coupling. Biophysical Journal 76 (1999), 1725–1733.

    PubMed  Google Scholar 

  30. Oehler, S., E.R. Eismann, H. Kramer and B. Mullerhill.: The 3 Operators of the Lac Operon Cooperate in Repression. Embo J. 9 (1990), 973–979.

    PubMed  Google Scholar 

  31. Goyal, S. Personal Communication. (2005).

  32. Buchler, N. E., U. Gerland and T. Hwa.: On schemes of combinatorial transcription logic. Proc. Natl. Acad. Sci. U.S.A. 100 (2003), 5136–5141.

    Article  PubMed  ADS  Google Scholar 

  33. Zeller, R.W., J.D. Griffith, J.G. Moore, C.V. Kirchhamer, R.J. Britten and E.H. Davidson.: A Multimerizing Transcription Factor of Sea-Urchin Embryos Capable of Looping DNA. Proceedings of the National Academy of Sciences of the United States of America 92 (1995), 2989–2993.

    Article  PubMed  ADS  Google Scholar 

  34. Bustamante, C., Z. Bryant and S.B. Smith.: Ten years of tension: single-molecule DNA mechanics. Nature 421 (2003), 423–427.

    Article  PubMed  ADS  Google Scholar 

  35. Finzi, L. and J. Gelles.: Measurement of Lactose Repressor-Mediated Loop Formation and Breakdown in Single DNA-Molecules. Science 267 (1995), 378–380.

    Article  PubMed  ADS  Google Scholar 

  36. Strick, T., J. Allemand, V. Croquette and D. Bensimon.: Twisting and stretching single DNA molecules. Prog Biophys Mol Biol 74 (2000), 115–140.

    Article  PubMed  Google Scholar 

  37. Nambiar, R., A. Gajraj and J.C. Meiners.: All-optical constant-force laser tweezers. Biophysical Journal 87 (2004), 1972–1980.

    Article  PubMed  Google Scholar 

  38. Lang, M.J., C.L. Asbury, J.W. Shaevitz and S.M. Block.: An automated two-dimensional optical force clamp for single molecule studies. Biophysical Journal 83 (2002), 491–501.

    PubMed  Google Scholar 

  39. Yan, J., D. Skoko and J.F. Marko.: Near-field-magnetic-tweezer manipulation of single DNA molecules. Physical Review E (2004), 70.

  40. Lia, G., D. Bensimon, V. Croquette, J.F. Allemand, D. Dunlap, D.E.A. Lewis, S.C. Adhya and L. Finzi.: Supercoiling and denaturation in Gal repressor/heat unstable nucleoid protein (HU)-mediated DNA looping. Proc. Natl. Acad. Sci. U.S.A. 100 (2003), 11373–11377.

    Article  PubMed  ADS  Google Scholar 

  41. Virnik, K., Y.L. Lyubchenko, M.A. Karymov, P. Dahlgren, M.Y. Tolstorukov, S. Semsey, V.B. Zhurkin and S. Adhya.: “Antiparallel” DNA Loop in Gal Repressosome Visualized by Atomic Force Microscopy. J. Mol. Biol. 334 (2003), 53–63.

    Article  PubMed  Google Scholar 

  42. Schafer, D.A., J. Gelles, M.P. Sheetz and R. Landick.: Transcription by Single Molecules of Rna-Polymerase Observed by Light-Microscopy. Nature 352 (1991), 444–448.

    Article  PubMed  ADS  Google Scholar 

  43. Yin, H., M.D. Wang, K. Svoboda, R. Landick, S.M. Block and J. Gelles.: Transcription against an Applied Force. Science 270 (1995), 1653–1657.

    Article  PubMed  ADS  Google Scholar 

  44. Strick, T.R., J.F. Allemand, D. Bensimon, A. Bensimon and V. Croquette.: The elasticity of a single supercoiled DNA molecule. Science 271 (1996), 1835–1837.

    Article  PubMed  ADS  Google Scholar 

  45. Poirier, M., S. Eroglu, D. Chatenay and J.F. Marko.: Reversible and irreversible unfolding of mitotic newt chromosomes by applied force. Molecular Biology of the Cell 11 (2000), 269–276.

    PubMed  Google Scholar 

  46. Ringrose, L., S. Chabanis, P.O. Angrand, C. Woodroofe and A.F. Stewart.: Quantitative comparison of DNA looping in vitro and in vivo: chromatin increases effective DNA flexibility at short distances. Embo J. 18 (1999), 6630–6641.

    Article  PubMed  Google Scholar 

  47. Rippe, K., P.H. Vonhippel and J. Langowski.: Action at a Distance – DNA-Looping and Initiation of Transcription. Trends in Biochemical Sciences 20 (1995), 500–506.

    Article  PubMed  Google Scholar 

  48. Leger, J.F., J. Robert, L. Bourdieu, D. Chatenay and J.F. Marko.: RecA binding to a single double-stranded DNA molecule: A possible role of DNA conformational fluctuations. Proceedings of the National Academy of Sciences of the United States of America 95 (1998), 12295–12299.

    Article  PubMed  ADS  Google Scholar 

  49. Marko, J.F. and M.G. Poirier.: Micromechanics of chromatin and chromosomes. Biochemistry and Cell Biology-Biochimie Et Biologie Cellulaire 81 (2003), 209–220.

    Article  PubMed  Google Scholar 

  50. Cluzel, P., A. Lebrun, C. Heller, R. Lavery, J.L. Viovy, D. Chatenay and F. Caron.: DNA: An extensible molecule. Science 271 (1996), 792–794.

    Article  PubMed  ADS  Google Scholar 

  51. Smith, S.B., Y.J. Cui and C. Bustamante.: Overstretching B-DNA: The elastic response of individual double-stranded and single-stranded DNA molecules. Science 271 (1996), 795–799.

    Article  PubMed  ADS  Google Scholar 

  52. Thanbichler, M., P.H. Viollier and L. Shapiro.: The structure and function of the bacterial chromosome. Current Opinion in Genetics & Development 15 (2005), 153–162.

    Article  Google Scholar 

  53. Misteli, T.: Concepts in nuclear architecture. Bioessays 27 (2005), 477–487.

    Article  PubMed  Google Scholar 

  54. Dworkin, J. and R. Losick.: Does RNA polymerase help drive chromosome segregation in bacteria? Proc. Natl. Acad. Sci. U.S.A. 99 (2002), 14089–14094.

    Article  PubMed  ADS  Google Scholar 

  55. Poirier, M.G. and J.F. Marko.: Mitotic chromosomes are chromatin networks without a mechanically contiguous protein scaffold. Proceedings of the National Academy of Sciences of the United States of America 99 (2002), 15393–15397.

    Article  PubMed  ADS  Google Scholar 

  56. Pederson, T.: Half a century of “the nuclear matrix”. Molecular Biology of the Cell 11 (2000), 799–805.

    PubMed  Google Scholar 

  57. Hancock, R.: Internal organisation of the nucleus: assembly of compartments by macromolecular crowding and the nuclear matrix model. Biology of the Cell 96 (2004), 595–601.

    Article  PubMed  Google Scholar 

  58. Shimada, J. and H. Yamakawa.: Ring-Closure Probabilities for Twisted Wormlike Chains –Application to DNA. Macromolecules 17 (1984), 689–698.

    Article  Google Scholar 

  59. Shore, D., J. Langowski and R.L. Baldwin.: DNA Flexibility Studied by Covalent Closure of Short Fragments into Circles. Proceedings of the National Academy of Sciences of the United States of America-Biological Sciences 78 (1981), 4833–4837.

    Article  Google Scholar 

  60. Popov, Y.O. and A.V. Tkachenko.: Effects of kinks on DNA elasticity. Physical Review E (Statistical, Nonlinear, and Soft Matter Physics) 71 (2005), 051905–051908.

    ADS  MathSciNet  Google Scholar 

  61. Wiggins, P. A., R. Phillips and P.C. Nelson.: Exact theory of kinkable elastic polymers. Physical Review E 71 (2005), 021909.

    Google Scholar 

  62. Yan, J. and J.F. Marko. Localized single-stranded bubble mechanism for cyclization of short double helix DNA. Physical Review Letters 93 (2004), 108108.

    Google Scholar 

  63. Dunn, T. M., S. Hahn, S. Ogden and R.F. Schleif.: An Operator at -280 Base-Pairs That Is Required for Repression of Arabad Operon Promoter – Addition of DNA Helical Turns between the Operator and Promoter Cyclically Hinders Repression. Proceedings of the National Academy of Sciences of the United States of America-Biological Sciences 81 (1984), 5017–5020.

    Article  Google Scholar 

  64. Muller, J., S. Oehler and B. Muller-Hill.: Repression of lac Promoter as a Function of Distance, Phase and Quality of an Auxiliary lac Operator. J. Mol. Biol. 257 (1996), 21–29.

    Article  PubMed  Google Scholar 

  65. Urnov, F.D. and A.P. Wolffe.: Above and within the genome: Epigenetics past and present. Journal of Mammary Gland Biology and Neoplasia 6 (2001), 153–167.

    Article  PubMed  Google Scholar 

  66. Ogata, K., K. Sato and T. Tahirov.: Eukaryotic transcriptional regulatory complexes: cooperativity from near and afar. Curr. Opin. Struct. Biol. 13 (2003), 40–48.

    Article  PubMed  Google Scholar 

  67. Vilar, J.M.G. and S. Leibler.: DNA looping and physical constraints on transcription regulation. Journal of Molecular Biology 331 (2003), 981–989.

    Article  PubMed  Google Scholar 

  68. Balaeff, A., L. Mahadevan and K. Schulten. Structural Basis for Cooperative DNA Binding by CAP and Lac Repressor. Structure 12 (2004), 123–132.

    Article  PubMed  Google Scholar 

  69. Kulic, I.M. and H. Schiessel.: DNA spools under tension. Physical Review Letters 92 (2004), 228101.

    Google Scholar 

  70. Levchenko, V., B. Jackson and V. Jackson.: Histone release during transcription: displacement of the two H2A-H2B dimers in the nucleosome is dependent on different levels of transcription-induced positive stress. Biochemistry 44 (2005), 5357–5372.

    Article  PubMed  Google Scholar 

  71. Hizume, K., S.H. Yoshimura and K. Takeyasu.: Atomic force microscopy demonstrates a critical role of DNA superhelicity in nucleosome dynamics. Cell Biochemistry and Biophysics 40 (2004), 249–261.

    Article  PubMed  Google Scholar 

  72. Jackson, S., W. Brooks and V. Jackson.: Dynamics of the Interactions of Histones H2a,H2b and H3,H4 with Torsionally Stressed DNA. Biochemistry 33 (1994), 5392–5403.

    Article  PubMed  Google Scholar 

  73. Mehta, R.A. and J.D. Kahn.: Designed hyperstable lac repressor center dot DNA loop topologies suggest alternative loop geometries. J. Mol. Biol. 294 (1999), 67–77.

    Article  PubMed  Google Scholar 

  74. Watson, M.A., D.M. Gowers and S.E. Halford.: Alternative geometries of DNA looping: an analysis using the SfiI endonuclease. J. Mol. Biol. 298 (2000), 461–475.

    Article  PubMed  Google Scholar 

  75. Zhang, Y.L. and D.M. Crothers.: Statistical mechanics of sequence-dependent circular DNA and its application for DNA cyclization. Biophysical Journal 84 (2003), 136–153.

    Article  PubMed  Google Scholar 

  76. Merlitz, H., K. Rippe, K.V. Klenin and J. Langowski.: Looping Dynamics of Linear DNA Molecules and the Effect of DNA Curvature: A Study by Brownian Dynamics Simulation. Biophys. J. 74 (1998), 773–779.

    PubMed  Google Scholar 

  77. Kessler, D.A. and Y. Rabin.: Effect of curvature and twist on the conformations of a fluctuating ribbon. J. Chem. Phys. 118 (2003), 897–904.

    Article  ADS  Google Scholar 

  78. Goyal, S., N.C. Perkins and C.L. Lee. Nonlinear dynamics and loop formation in Kirchhoff rods with implications to the mechanics of DNA and cables. Journal of Computational Physics 209 (2005), 371–389.

    Google Scholar 

  79. Marko, J.F. and E.D. Siggia.: Fluctuations and Supercoiling of DNA. Science. 265 (1994), 506–508.

    Article  PubMed  ADS  Google Scholar 

  80. Jian, H., T. Schlick and A. Vologodskii.: Internal Motion of Supercoiled DNA: Brownian Dynamics Simulations of Site Juxtaposition. J. Mol. Biol. 284 (1998), 287–296.

    Article  PubMed  Google Scholar 

  81. Huang, J., T. Schlick and A. Vologodskii.: Dynamics of site juxtaposition in supercoiled DNA. Proceedings of the National Academy of Sciences of the United States of America. 98 (2001), 968–973.

    Article  PubMed  ADS  Google Scholar 

  82. Stanford, N.P., M.D. Szczelkun, J.F. Marko and S.E. Halford.: One- and three-dimensional pathways for proteins to reach specific DNA sites. Embo J. 19 (2000), 6546–6557.

    Article  PubMed  Google Scholar 

  83. Embleton, M.L., A.V. Vologodskii and S.E. Halford.: Dynamics of DNA Loop Capture by the SfiI Restriction Endonuclease on Supercoiled and Relaxed DNA. J. Mol. Bio. 339 (2004), 53–66.

    Article  Google Scholar 

  84. Bussiek, M., K. Klenin and J. Langowski.: Kinetics of site-site interactions in Supercoiled DNA with bent sequences. J. Mol. Biol. 322 (2002), 707–718.

    Article  PubMed  Google Scholar 

  85. Pfannschmidt, C. and J. Langowski. Superhelix organization by DNA curvature as measured through site-specific labeling. J Mol Biol. 275 (1998), 601–611.

    Article  PubMed  Google Scholar 

  86. Yang, Y., T.P. Westcott, S.C. Pedersen, I. Tobias and W.K. Olson.: Effects of Localized Bending on DNA Supercoiling. Trends in Biochemical Sciences 20 (1995), 313–319.

    Article  PubMed  Google Scholar 

  87. Travers, A. and G. Muskhelishvili.: DNA supercoiling - a global transcriptional regulator for enterobacterial growth? Nature Reviews – Microbiology 3 (2005), 157–169.

    Article  PubMed  Google Scholar 

  88. Krasilnikov, A.S., A. Podtelezhnikov, A. Vologodskii and S. M. Mirkin.: Large-scale Effects of Transcriptional DNA Supercoiling in Vivo. J. Mol. Bio. 292 (1999), 1149–1160.

    Article  Google Scholar 

  89. Chen, C-C. and H-Y. Wu.: Transcription-driven DNA supercoiling and gene expression control. Frontiers in Bioscience 8 (2003), 430–439.

    Article  Google Scholar 

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  1. Department of Physics and Biophysics Research Division, Randall Laboratory, University of Michigan, Ann Arbor, MI, 48109-1120, USA

    Seth Blumberg, Matthew W. Pennington & Jens-Christian Meiners

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  1. Seth Blumberg
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  3. Jens-Christian Meiners
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Blumberg, S., Pennington, M.W. & Meiners, JC. Do Femtonewton Forces Affect Genetic Function? A Review. J Biol Phys 32, 73–95 (2006). https://doi.org/10.1007/s10867-005-9002-8

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