How Proteins Slide on DNA

  • Daniel Barsky
  • Ted A. Laurence
  • Česlovas Venclovas
Part of the Biological and Medical Physics, Biomedical Engineering book series (BIOMEDICAL)


Protein–DNA interactions are required for all the major functions of DNA: ­transcription and regulation, replication and repair, even the packaging of DNA into chromosomes. Not only are protein–DNA interactions crucial for all these cellular activities, but they are also, in our view, among the most fascinating macromolecular­ interactions because of their dynamics. In this chapter, we focus on DNA sliding by proteins, particularly diffusive sliding. Such sliding is typically part of the search for a target on the DNA itself or for another protein bound to the DNA. Of particular interest here are the proteins known as DNA sliding clamps that can remain bound to the DNA while diffusing vast distances along the double helix of DNA. We do not yet know the detailed mechanisms of protein sliding on DNA, but we aim to familiarize the reader with what is known observationally and to provide some discussion of potential mechanisms.


Fluorescence Resonance Energy Transfer Diffusion Constant Total Internal Reflection Fluorescence lacI Repressor Fluorescence Resonance Energy Transfer Efficiency 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    Berg OG, Winter RB, Vonhippel PH (1981) Diffusion-driven mechanisms of protein translocation on nucleic-acids. 1. Models and theory. Biochemistry 20:6929–6948CrossRefGoogle Scholar
  2. 2.
    Adam G, Delbrück M (1968) Reduction of dimensionality in biological diffusion processes. In: Rich A, Davidson N (eds) Structural chemistry and molecular biology. W.H. Freeman and Company, San Francisco, pp 198–215Google Scholar
  3. 3.
    Riggs AD, Bourgeoi S, Cohn M (1970) The lac repressor–operator interaction. 3. Kinetic studies. J Mol Biol 53:401–417CrossRefGoogle Scholar
  4. 4.
    Winter RB, Vonhippel PH (1981) Diffusion-driven mechanisms of protein translocation on nucleic-acids. 2. The Escherichia coli repressor–operator interaction – equilibrium measurements. Biochemistry 20:6948–6960CrossRefGoogle Scholar
  5. 5.
    Winter RB, Berg OG, Vonhippel PH (1981) Diffusion-driven mechanisms of protein translocation on nucleic-acids. 3. The Escherichia coli lac repressor–operator interaction – kinetic measurements and conclusions. Biochemistry 20:6961–6977CrossRefGoogle Scholar
  6. 6.
    Slutsky M, Mirny LA (2004) Kinetics of protein–DNA interaction: facilitated target location in sequence-dependent potential. Biophys J 87:4021–4035CrossRefGoogle Scholar
  7. 7.
    Halford SE, Marko JF (2004) How do site-specific DNA-binding proteins find their targets? Nucleic Acids Res 32:3040–3052CrossRefGoogle Scholar
  8. 8.
    Greenleaf WJ, Woodside MT, Block SM (2007) High-resolution, single-molecule measurements of biomolecular motion. Annu Rev Biophys Biomol Struct 36:171–190CrossRefGoogle Scholar
  9. 9.
    Herbert KM, Greenleaf WJ, Block SM (2008) Single-molecule studies of RNA polymerase: motoring along. Annu Rev Biochem 77:149–176CrossRefGoogle Scholar
  10. 10.
    Wunderlich Z, Mirny LA (2008) Spatial effects on the speed and reliability of protein–DNA search. Nucleic Acids Res 36:3570–3578CrossRefGoogle Scholar
  11. 11.
    Laurence TA, Kwon Y, Johnson A, Hollars CW, O’Donnell M, Camarero JA, Barsky D (2008) Motion of a DNA sliding clamp observed by single molecule fluorescence spectroscopy. J Biol Chem 283:22895–22906CrossRefGoogle Scholar
  12. 12.
    Maki S, Kornberg A (1988) DNA polymerase III holoenzyme of Escherichia coli. 3. Distinctive processive polymerases reconstituted from purified subunits. J Biol Chem 263:6561–6569Google Scholar
  13. 13.
    Yao NY, O’Donnell M (2009) Replisome structure and conformational dynamics underlie fork progression past obstacles. Curr Opin Cell Biol 21:336–343CrossRefGoogle Scholar
  14. 14.
    Gowers DM, Halford SE (2003) Protein motion from non-specific to specific DNA by three-dimensional routes aided by supercoiling. EMBO J 22:1410–1418CrossRefGoogle Scholar
  15. 15.
    Yao N, Turner J, Kelman Z, Stukenberg PT, Dean F, Shechter D, Pan ZQ, Hurwitz J, Odonnell M (1996) Clamp loading, unloading and intrinsic stability of the PCNA, beta and gp45 sliding clamps of human, E. coli and T4 replicases. Genes Cells 1:101–113CrossRefGoogle Scholar
  16. 16.
    Redner S (2001) A guide to first-passage processes. Cambridge University Press, CambridgeMATHCrossRefGoogle Scholar
  17. 17.
    Austin RH, Karohl J, Jovin TM (1983) Rotational diffusion of Escherichia coli RNA polymerase free and bound to deoxyribonucleic acid in nonspecific complexes. Biochemistry 22:3082–3090CrossRefGoogle Scholar
  18. 18.
    Gorman J, Chowdhury A, Surtees JA, Shimada J, Reichman DR, Alani E, Greene EC (2007) Dynamic basis for one-dimensional DNA scanning by the mismatch repair complex Msh2–Msh6. Mol Cell 28:359–370CrossRefGoogle Scholar
  19. 19.
    Gorman J, Greene EC (2008) Visualizing one-dimensional diffusion of proteins along DNA. Nat Struct Mol Biol 15:768–774CrossRefGoogle Scholar
  20. 20.
    Biebricher A, Wende W, Escude C, Pingoud A, Desbiolles P (2009) Tracking of single quantum dot labeled EcoRV sliding along DNA manipulated by double optical tweezers. Biophys J 96:L50–L52CrossRefGoogle Scholar
  21. 21.
    Bonnet I, Biebricher A, Porte PL, Loverdo C, Benichou O, Voituriez R, Escude C, Wende W, Pingoud A, Desbiolles P (2008) Sliding and jumping of single EcoRV restriction enzymes on non-cognate DNA. Nucleic Acids Res 36:4118–4127CrossRefGoogle Scholar
  22. 22.
    Blainey PC, van Oijent AM, Banerjee A, Verdine GL, Xie XS (2006) A base-excision DNA-repair protein finds intrahelical lesion bases by fast sliding in contact with DNA. Proc Natl Acad Sci USA 103:5752–5757ADSCrossRefGoogle Scholar
  23. 23.
    Harada Y, Funatsu T, Murakami K, Nonoyama Y, Ishihama A, Yanagida T (1999) Single-molecule imaging of RNA polymerase–DNA interactions in real time. Biophys J 76:709–715CrossRefGoogle Scholar
  24. 24.
    Kochaniak AB, Habuchi S, Loparo JJ, Chang DJ, Cimprich KA, Walter JC, van Oijen AM (2009) Proliferating cell nuclear antigen uses two distinct modes to move along DNA. J Biol Chem 284:17700–17710CrossRefGoogle Scholar
  25. 25.
    Lin Y, Zhao T, Jian X, Farooqui Z, Qu X, He C, Dinner AR, Scherer NF (2009) Using the bias from flow to elucidate single DNA repair protein sliding and interactions with DNA. Biophys J 96:1911–1917CrossRefGoogle Scholar
  26. 26.
    Tafvizi A, Huang F, Leith JS, Fersht AR, Mirny LA, van Oijen AM (2008) Tumor suppressor p53 slides on DNA with low friction and high stability. Biophys J 95:L1–L3CrossRefGoogle Scholar
  27. 27.
    Wang YM, Austin RH, Cox EC (2006) Single molecule measurements of repressor protein 1D diffusion on DNA. Phys Rev Lett 97:4Google Scholar
  28. 28.
    Liu SX, Abbondanzieri EA, Rausch JW, Le Grice SFJ, Zhuang XW (2008) Slide into action: dynamic shuttling of HIV reverse transcriptase on nucleic acid substrates. Science 322:1092–1097ADSCrossRefGoogle Scholar
  29. 29.
    Roy R, Kozlov AG, Lohman TM, Ha T (2009) SSB protein diffusion on single-stranded DNA stimulates RecA filament formation. Nature 461:1092–1097ADSCrossRefGoogle Scholar
  30. 30.
    Rau DC, Sidorova NY (2010) Diffusion of the restriction nuclease EcoRI along DNA. J Mol Biol 395:408–416CrossRefGoogle Scholar
  31. 31.
    Blainey PC, Luo GB, Kou SC, Mangel WF, Verdine GL, Bagchi B, Xie XS (2009) Nonspecifically bound proteins spin while diffusing along DNA. Nat Struct Mol Biol 16:1224–1229CrossRefGoogle Scholar
  32. 32.
    Graneli A, Yeykal CC, Robertson RB, Greene EC (2006) Long-distance lateral diffusion of human Rad51 on double-stranded DNA. Proc Natl Acad Sci USA 103:1221–1226ADSCrossRefGoogle Scholar
  33. 33.
    Laurence TA, Kwon Y, Yin E, Hollars CW, Camarero JA, Barsky D (2007) Correlation spectroscopy of minor fluorescent species: signal purification and distribution analysis. Biophys J 92:2184–2198CrossRefGoogle Scholar
  34. 34.
    Kampmann M (2004) Obstacle bypass in protein motion along DNA by two-dimensional rather than one-dimensional sliding. J Biol Chem 279:38715–38720CrossRefGoogle Scholar
  35. 35.
    Kong XP, Onrust R, Odonnell M, Kuriyan J (1992) Three-dimensional structure of the beta-subunit of Escherichia coli DNA polymerase III holoenzyme – a sliding DNA clamp. Cell 69:425–437CrossRefGoogle Scholar
  36. 36.
    García De La Torre J, Huertas M, Carrasco B (2000) Calculation of hydrodynamic properties of globular proteins from their atomic-level structure. Biophys J 78:719–730CrossRefGoogle Scholar
  37. 37.
    Schurr J (1979) The one-dimensional diffusion coefficient of proteins absorbed on DNA hydrodynamic considerations. Biophys Chem 9:413–414CrossRefGoogle Scholar
  38. 38.
    Bagchi B, Blainey PC, Xie XS (2008) Diffusion constant of a nonspecifically bound protein undergoing curvilinear motion along DNA. J Phys Chem B 112:6282–6284CrossRefGoogle Scholar
  39. 39.
    Zwanzig R (1988) Diffusion in a rough potential. Proc Natl Acad Sci USA 85:2029–2030MathSciNetADSCrossRefGoogle Scholar
  40. 40.
    Barbi M, Place C, Popkov V, Salerno M (2004) A model of sequence-dependent protein ­diffusion along DNA. J Biol Phys 30:203–226CrossRefGoogle Scholar
  41. 41.
    Johnson A, O’Donnell M (2005) Cellular DNA replicases: components and dynamics at the replication fork. Annu Rev Biochem 74:283–315CrossRefGoogle Scholar
  42. 42.
    Fay P, Johanson K, McHenry C, Bambara R (1981) Size classes of products synthesized ­processively by DNA polymerase III and DNA polymerase III holoenzyme of Escherichia coli. J Biol Chem 256:976–983Google Scholar
  43. 43.
    Indiani C, McInerney P, Georgescu R, Goodman M, O’Donnell M (2005) A sliding-clamp toolbelt binds high- and low-fidelity DNA polymerases simultaneously. Mol Cell 19:805–815CrossRefGoogle Scholar
  44. 44.
    Indiani C, Langston LD, Yurieva O, Goodman MF, O’Donnell M (2009) Translesion DNA polymerases remodel the replisome and alter the speed of the replicative helicase. Proc Natl Acad Sci USA 106:6031–6038ADSCrossRefGoogle Scholar
  45. 45.
    Adzuma K (1998) No sliding during homology search by RecA protein. J Biol Chem 273:31565–31573CrossRefGoogle Scholar
  46. 46.
    Hu LH, Grosberg AY, Bruinsma R (2008) Are DNA transcription factor proteins Maxwellian Demons? Biophys J 95:1151–1156CrossRefGoogle Scholar
  47. 47.
    Jeltsch A, Alves J, Wolfes H, Maass G, Pingoud A (1994) Pausing of the restriction-endonuclease EcoRI during linear diffusion on DNA. Biochemistry 33:10215–10219CrossRefGoogle Scholar
  48. 48.
    Jones S, van Heyningen P, Berman HM, Thornton JM (1999) Protein–DNA interactions: a structural analysis. J Mol Biol 287:877–896CrossRefGoogle Scholar
  49. 49.
    Georgescu RE, Kim SS, Yurieva O, Kuriyan J, Kong XP, O’Donnell M (2008) Structure of a sliding clamp on DNA. Cell 132:43–54CrossRefGoogle Scholar
  50. 50.
    Holbrook JA, Tsodikov OV, Saecker RM, Record MT (2001) Specific and non-specific interactions of integration host factor with DNA: thermodynamic evidence for disruption of ­multiple IHF surface salt-bridges coupled to DNA binding. J Mol Biol 310:379–401CrossRefGoogle Scholar
  51. 51.
    McNally R, Bowman GD, Goedken ER, O’Donnell M, Kuriyan J (2010) Analysis of the role of PCNA-DNA contacts during clamp loading. BMC Struct Biol 10:3CrossRefGoogle Scholar
  52. 52.
    Mayanagia K, Kiyonari S, Saito M, Shirai T, Ishino Y, Morikawa K (2009) Mechanism of replication machinery assembly as revealed by the DNA ligase-PCNA–DNA complex architecture. Proc Natl Acad Sci USA 106:4647–4652ADSCrossRefGoogle Scholar
  53. 53.
    Ivanov I, Chapados BR, McCammon JA, Tainer JA (2006) Proliferating cell nuclear antigen loaded onto double-stranded DNA: dynamics, minor groove interactions and functional implications. Nucleic Acids Res 34:6023–6033CrossRefGoogle Scholar
  54. 54.
    Winter JA, Christofi P, Morroll S, Bunting KA (2009) The crystal structure of Haloferax volcanii proliferating cell nuclear antigen reveals unique surface charge characteristics due to halophilic adaptation. BMC Struct Biol 9:55CrossRefGoogle Scholar
  55. 55.
    Morgunova E, Gray FC, MacNeill SA, Ladenstein R (2009) Structural insights into the adaptation of proliferating cell nuclear antigen (PCNA) from Haloferax volcanii to a high-salt environment. Acta Crystallogr D Biol Crystallogr 65:1081–1088CrossRefGoogle Scholar
  56. 56.
    Yao N, Hurwitz J, O’Donnell M (2000) Dynamics of beta and proliferating cell nuclear antigen­ sliding clamps in traversing DNA secondary structure. J Biol Chem 275:1421–1432CrossRefGoogle Scholar
  57. 57.
    Dahirel V, Paillusson F, Jardat M, Barbi M, Victor JM (2009) Nonspecific DNA–protein interaction: why proteins can diffuse along DNA. Phys Rev Lett 102:4CrossRefGoogle Scholar
  58. 58.
    Sun J, Viadiu H, Aggarwal AK, Weinstein H (2003) Energetic and structural considerations for the mechanism of protein sliding along DNA in the nonspecific BamHI–DNA complex. Biophys J 84:3317–3325CrossRefGoogle Scholar
  59. 59.
    Halford SE (2009) An end to 40 years of mistakes in DNA-protein association kinetics? Biochem Soc Trans 37:343–348CrossRefGoogle Scholar
  60. 60.
    Doucleff M, Clore GM (2008) Global jumping and domain-specific intersegment transfer between DNA cognate sites of the multidomain transcription factor Oct-1. Proc Natl Acad Sci USA 105:13871–13876ADSCrossRefGoogle Scholar
  61. 61.
    Nowarski R, Britan-Rosich E, Shiloach T, Kotler M (2008) Hypermutation by intersegmental transfer of APOBEC3G cytidine deaminase. Nat Struct Mol Biol 15:1059–1066CrossRefGoogle Scholar
  62. 62.
    Luscombe NM, Laskowski RA, Thornton JM (1997) NUCPLOT: a program to generate ­schematic diagrams of protein–nucleic acid interactions. Nucleic Acids Res 25:4940–4945CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Daniel Barsky
    • 1
  • Ted A. Laurence
  • Česlovas Venclovas
  1. 1.Physical and Life Sciences Directorate, Lawrence Livermore National LaboratoryLivermoreUSA

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