Strong physical constraints on sequence-specific target location by proteins on DNA molecules

Flyvbjerg, Henrik; Keatch, Steven A.; Dryden, David T. F.

doi:10.1093/nar/gkl271

Cited by 36 publications

(56 citation statements)

References 52 publications

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“…Note that, in the Additional file 1: Supplementary Material , the accuracy of this estimate is systematically investigated in the case of DNA crowding. The results confirm that for a DNA occupancy up to 50% (as in the case of E.coli [19]) the equation displays negligible errors.…”

Section: Resultssupporting

confidence: 80%

System size reduction in stochastic simulations of the facilitated diffusion mechanism

Zabet

2012

BMC Systems Biology

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BackgroundSite-specific Transcription Factors (TFs) are proteins that bind to specific sites on the DNA and control the activity of a target gene by enhancing or decreasing the rate at which the gene is transcribed by RNA polymerase. The process by which TF molecules locate their target sites is a key component of transcriptional regulation. Therefore it is essential to gain insight into the mechanisms by which TFs search for the target sites.Research in this area uses experimental and analytical approaches, but also stochastic simulations of the search process. Previous work based on stochastic simulations focussed only on short sequences, primarily for reasons of technical feasibility. Many of these studies had to disregard possible biases introduced by reducing a genome-wide system to a smaller subsystem. In particular, we identified crucial parameters that require adjustment, which were not adequately changed in these previous studies.ResultsWe investigated several methods that adequately adapt the parameters of stochastic simulations of the facilitated diffusion, when the full sequence space is reduced to smaller regions of interest. We found two methods that scale the system accordingly: the copy number model and the association rate model. We systematically compared the results produced by simulations of the subsystem with respect to the original system. Our results confirmed that the copy number model is adequate only for high abundance TFs, while for low abundance TFs the association rate model is the only one that reproduces with high accuracy the results of the full system.ConclusionsWe propose a strategy to reduce the size of the system that adequately adapts important parameters to capture the behaviour of the full system. This enables correct simulations of a smaller sequence space (which can be as small as 100 Kbp) and, thus, provides independence from computationally intensive genome-wide simulations of the facilitated diffusion mechanism.

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Section: Resultssupporting

confidence: 80%

System size reduction in stochastic simulations of the facilitated diffusion mechanism

Zabet

2012

BMC Systems Biology

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“…The period icity of nucleosome arrangement decays with increas ing distance from the boundary. Such boundary effects are not specific to nucleosomes and have also been predicted and observed for the general case of pro tein-DNA binding [84][85][86]. Recent experiments [53,[87][88][89] and theoretical investigations [39,90] con firmed the importance of boundary effects for nucleo some positioning.…”

Section: Lattice Modelsmentioning

confidence: 69%

Nucleosomes in gene regulation: Theoretical approaches

et al. 2012

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This work reviews current theoretical approaches of biophysics and bioinformatics for the descrip tion of nucleosome arrangements in chromatin and transcription factor binding to nucleosomal organized DNA. The role of nucleosomes in gene regulation is discussed from the molecular mechanistic and biologi cal points of view. In addition to classical problems in this field, actual questions of epigenetic regulation are discussed. The authors selected for discussion what seem to be the most interesting concepts and hypotheses. Mathematical approaches are described in a simplified language to attract attention to the most important directions of this field.

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“…However, the rate of target site location then fell steeply as the sliding length was further increased, with a 10-fold increase in sliding length causing a 10-fold decrease in the association rate to the specific site [13]. Numerous subsequent analyses employing a wide variety of mathematical and physical procedures of varying degrees of rigour have concurred with this view (among many others, [31][32][33][34][35]). There thus seems to be a general consensus that the rate of target site location is optimized by including both 1D and 3D steps.…”

Section: Is 1d or 3d The Quickest Route To The Target?mentioning

confidence: 93%

An end to 40 years of mistakes in DNA–protein association kinetics?

Halford

2009

Biochemical Society Transactions

208

245

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Proteins that bind to specific sequences in long DNA molecules have to locate their target sites amid myriad alternative sequences, yet they do so at remarkably rapid rates, sometimes approaching 10(10) M(-1) x s(-1). Hence, it has been asserted widely that binding to specific DNA sites can surpass the maximal rate for 3D (three-dimensional) diffusion through solution and that this could only be accounted for by a reduction in the dimensionality of the search for the target in effect by 1D (one-dimensional) diffusion (or 'sliding') along the DNA contour. It will be shown here that there is, in fact, no known example of a protein binding to a specific DNA site at a rate above the diffusion limit, and that the rapidity of these reactions is due primarily to electrostatic interactions between oppositely charged molecules. It will also be shown that, contrary to popular belief, reduced dimensionality does not, in general, increase the rate of target-site location but instead reduces it. Finally, it will be demonstrated that proteins locate their target sites primarily by multiple dissociation/reassociation events to other (nearby or distant) sites within the same DNA molecule, and that 1D diffusion is limited to local searches covering approximately 50 bp around each landing site.

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Strong physical constraints on sequence-specific target location by proteins on DNA molecules

Cited by 36 publications

References 52 publications

System size reduction in stochastic simulations of the facilitated diffusion mechanism

System size reduction in stochastic simulations of the facilitated diffusion mechanism

Nucleosomes in gene regulation: Theoretical approaches

An end to 40 years of mistakes in DNA–protein association kinetics?

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