R. Metzler (University of Munich, Germany)
Role of DNA Conformation in Gene Control

Leiden University - Friday 4 July at 10.00 hrs
De Sitterzaal - Oortbuilding

Genes are regulated through binding of so-called transcription factors to specific sites on the DNA. To find its specific binding site such a DNA binding protein needs to scan megabases of DNA inside the cell. According to the Berg-von Hippel model [1] this search comprises volume diffusion with one-dimensional diffusion along the DNA mediated through non-specific binding [2]. An additional mechanism are intersegmental jumps in which the binding protein can jump from one segment of the DNA to a chemically remote segment that is close by in the embedding space due to DNA looping (e.g., bacterial DNA is of the length of several mm and on larger scales corresponds to a flexible  polymer [3]. The binding dynamics of proteins to DNA can be probed on the level of single molecules [4]. The influence of the DNA conformation on the search efficiency of the transcription factors will be analysed. It will be shown that for long DNA chains under typical in vitro conditions intersegmental jumps help improving the search efficiency and actually give rise to Levy flights along the DNA backbone [5]. These claims are confirmed by recent single molecule experiments in which the protein binding rate was measured versus the degree to which the DNA was allowed to relax conformationally [6]. In vivo the high degree of molecular crowding appears to significantly change the relative dynamics of the various search mechanisms in the Berg-von Hippel model. Some aspects of these changes will be addressed, in particular the effected more local nature of gene regulation [7]. The talk will close with some remarks on the interpretation of single particle tracking data of diffusion processes in complex environments [8].

References:
[1]   P.H. von Hippel and O.G. Berg, J. Biol. Chem. 264, 675 (1989).
[2]   See, for instance, A. Bakk and R. Metzler, FEBS Lett. 563, 66 (2004); J. Theor. Biol. 231, 525 (2004).
[3]   R. Metzler, T. Ambjornsson, A. Hanke, and S. Levene, Single DNA conformations and biological function. J. Comp. Theor. Nanoscience 4, 1 (2007); E-print physics/0609139.
[4]   I.M. Sokolov, R. Metzler, K. Pant, and M.C. Williams, Biophys. J. 89, 895 (2005); Y.M. Wang, R.H. Austin, and E.C. Cox, Phys. Rev. Lett. 97, 048302 (2006).
[5]   M.A. Lomholt, T. Ambjornsson, and R. Metzler, Phys. Rev. Lett. 95, 260603 (2005).
[6]   B. van den Broek, M.A. Lomholt, S.-M.J. Kalisch, R. Metzler, and G.J.L. Wuitte, submitted.
[7]   M.A. Lomholt, I.M. Zaid, and R. Metzler, Phys. Rev. Lett. 98, 200603 (2007).
[8]   Y. He, S. Burov, R. Metzler, and E. Barkai, Phys. Rev. Lett., at press.