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Facilitated diffusion on DNA

Fabian M Hecht, Andreas R Bausch
The self-organization of colloidal particles is a promising approach to create novel structures and materials, with applications spanning from smart materials to optoelectronics to quantum computation. However, designing and producing mesoscale-sized structures remains a major challenge because at length scales of 10-100 μm equilibration times already become prohibitively long. Here, we extend the principle of rapid diffusion-limited cluster aggregation (DLCA) to a multicomponent system of spherical colloidal particles to enable the rational design and production of finite-sized anisotropic structures on the mesoscale...
August 2, 2016: Proceedings of the National Academy of Sciences of the United States of America
Yago Nieto, Benigno C Valdez, Peter F Thall, Roy B Jones, Wei Wei, Alan Myers, Chitra Hosing, Sairah Ahmed, Uday Popat, Elizabeth J Shpall, Muzaffar Qazilbash, Alison Gulbis, Paolo Anderlini, Nina Shah, Qaiser Bashir, Amin Alousi, Yasuhiro Oki, Michelle Fanale, Bouthaina Dabaja, Chelsea Pinnix, Richard Champlin, Borje S Andersson
BACKGROUND: More active high-dose chemotherapy (HDC) regimens are needed for refractory lymphomas. The authors previously combined infusional gemcitabine with busulfan and melphalan (Gem/Bu/Mel) pursuing DNA damage repair inhibition. Subsequently, they combined Gem/Bu/Mel with vorinostat, which facilitates chemotherapy access to DNA. The resulting regimen was safe and synergistic. However, vorinostat induced DNA methyltransferase up-regulation, which could be preclinically abrogated by azacitidine, increasing tumor-cell kill...
September 1, 2016: Cancer
Iris Dror, Remo Rohs, Yael Mandel-Gutfreund
Transcription factors (TFs) have to find their binding sites, which are distributed throughout the genome. Facilitated diffusion is currently the most widely accepted model for this search process. Based on this model the TF alternates between one-dimensional sliding along the DNA, and three-dimensional bulk diffusion. In this view, the non-specific associations between the proteins and the DNA play a major role in the search dynamics. However, little is known about how the DNA properties around the motif contribute to the search...
July 2016: BioEssays: News and Reviews in Molecular, Cellular and Developmental Biology
Lorenz Keil, Michael Hartmann, Simon Lanzmich, Dieter Braun
How can living matter arise from dead matter? All known living systems are built around information stored in RNA and DNA. To protect this information against molecular degradation and diffusion, the second law of thermodynamics imposes the need for a non-equilibrium driving force. Following a series of successful experiments using thermal gradients, we have shown that heat gradients across sub-millimetre pores can drive accumulation, replication, and selection of ever longer molecules, implementing all the necessary parts for Darwinian evolution...
July 27, 2016: Physical Chemistry Chemical Physics: PCCP
David Gomez, Stefan Klumpp
Biological functions of DNA depend on the sequence-specific binding of DNA-binding proteins to their corresponding binding sites. Binding of these proteins to their binding sites occurs through a facilitated diffusion process that combines three-dimensional diffusion in the cytoplasm with one-dimensional diffusion (sliding) along the DNA. In this work, we use a lattice model of facilitated diffusion to study how the dynamics of binding of a protein to a specific site (e.g., binding of an RNA polymerase to a promoter or of a transcription factor to its operator site) is affected by the presence of other proteins bound to the DNA, which act as 'obstacles' in the sliding process...
April 28, 2016: Physical Chemistry Chemical Physics: PCCP
Yiding Ma, Yuhao Chen, Wancheng Yu, Kaifu Luo
We investigate how a tracer particle searches a target located in DNA modeled by a stiff chain in crowded environments using theoretical analysis and Langevin dynamics simulations. First, we show that the three-dimensional (3D) diffusion coefficient of the tracer only depends on the density of crowders ϕ, while its one-dimensional (1D) diffusion coefficient is affected by not only ϕ but also the nonspecific binding energy ε. With increasing ϕ and ε, no obvious change in the average 3D diffusion time is observed, while the average 1D sliding time apparently increases...
March 28, 2016: Journal of Chemical Physics
Diogo Martins, Xi Wei, Rastislav Levicky, Yong-Ak Song
UNLABELLED: We describe a microfluidic concentration device to accelerate the surface hybridization reaction between DNA and morpholinos (MOs) for enhanced detection. The microfluidic concentrator comprises a single polydimethylsiloxane (PDMS) microchannel onto which an ion-selective layer of conductive polymer poly(3,4-ethylenedioxythiophene)-poly(styrenesulfonate) ( PEDOT: PSS) was directly printed and then reversibly surface bonded onto a morpholino microarray for hybridization...
April 5, 2016: Analytical Chemistry
Tien Anh Ngo, Eiji Nakata, Masayuki Saimura, Takashi Morii
We report the construction of an artificial enzyme cascade based on the xylose metabolic pathway. Two enzymes, xylose reductase and xylitol dehydrogenase, were assembled at specific locations on DNA origami by using DNA-binding protein adaptors with systematic variations in the interenzyme distances and defined numbers of enzyme molecules. The reaction system, which localized the two enzymes in close proximity to facilitate transport of reaction intermediates, resulted in significantly higher yields of the conversion of xylose into xylulose through the intermediate xylitol with recycling of the cofactor NADH...
March 9, 2016: Journal of the American Chemical Society
Xiuzhong Wang, Shanshan Dong, Ting Hou, Lei Liu, Xiaojuan Liu, Feng Li
A novel enzyme inhibition-based homogeneous electrochemical biosensing strategy was designed for an organophosphorus pesticide assay based on exploiting the resistance of a mercury ion-mediated helper probe (HP) toward nuclease-catalyzed digestion and the remarkable diffusivity difference between HPs and the mononucleotides toward a negatively charged indium tin oxide (ITO) electrode. In particular, the mercury ion-mediated T-Hg(2+)-T base pairs facilitate the HP labeled with methylene blue (MB) to fold into a hairpin structure, preventing its digestion by exonuclease I, and thus resulting in a low electrochemical response because of the large electrostatic repulsion between the negatively charged ITO electrode and the HPs...
March 7, 2016: Analyst
Maxwell W Brown, Yoori Kim, Gregory M Williams, John D Huck, Jennifer A Surtees, Ilya J Finkelstein
DNA-binding proteins search for specific targets via facilitated diffusion along a crowded genome. However, little is known about how crowded DNA modulates facilitated diffusion and target recognition. Here we use DNA curtains and single-molecule fluorescence imaging to investigate how Msh2-Msh3, a eukaryotic mismatch repair complex, navigates on crowded DNA. Msh2-Msh3 hops over nucleosomes and other protein roadblocks, but maintains sufficient contact with DNA to recognize a single lesion. In contrast, Msh2-Msh6 slides without hopping and is largely blocked by protein roadblocks...
2016: Nature Communications
Walter F Mangel, William J McGrath, Kan Xiong, Vito Graziano, Paul C Blainey
Recently, we showed the adenovirus proteinase interacts productively with its protein substrates in vitro and in vivo in nascent virus particles via one-dimensional diffusion along the viral DNA. The mechanism by which this occurs has heretofore been unknown. We show sliding of these proteins along DNA occurs on a new vehicle in molecular biology, a 'molecular sled' named pVIc. This 11-amino acid viral peptide binds to DNA independent of sequence. pVIc slides on DNA, exhibiting the fastest one-dimensional diffusion constant, 26±1...
2016: Nature Communications
Marcin Tabaka, Krzysztof Burdzy, Robert Hołyst
DNA-binding protein searches for its target, a specific site on DNA, by means of diffusion. The search process consists of many recurrent steps of one-dimensional diffusion (sliding) along the DNA chain and three-dimensional diffusion (hopping) after dissociation of a protein from the DNA chain. Here we propose a computational method that allows extracting the contribution of sliding and hopping to the search process in vivo from the measurements of the kinetics of the target search by the lac repressor in Escherichia coli [P...
August 2015: Physical Review. E, Statistical, Nonlinear, and Soft Matter Physics
Ignacio F Gallardo, Praveenkumar Pasupathy, Maxwell Brown, Carol M Manhart, Dean P Neikirk, Eric Alani, Ilya J Finkelstein
Single-molecule studies of protein-DNA interactions have shed critical insights into the molecular mechanisms of nearly every aspect of DNA metabolism. The development of DNA curtains-a method for organizing arrays of DNA molecules on a fluid lipid bilayer-has greatly facilitated these studies by increasing the number of reactions that can be observed in a single experiment. However, the utility of DNA curtains is limited by the challenges associated with depositing nanometer-scale lipid diffusion barriers onto quartz microscope slides...
September 22, 2015: Langmuir: the ACS Journal of Surfaces and Colloids
Yaru Zhang, Patrick J O'Brien
Human alkyladenine DNA glycosylase (AAG) initiates the base excision repair pathway by excising alkylated and deaminated purine lesions. In vitro biochemical experiments demonstrate that AAG uses facilitated diffusion to efficiently search DNA to find rare sites of damage and suggest that electrostatic interactions are critical to the searching process. However, it remains an open question whether DNA searching limits the rate of DNA repair in vivo. We constructed AAG mutants with altered searching ability and measured their ability to protect yeast from alkylation damage in order to address this question...
November 20, 2015: ACS Chemical Biology
Jérôme Cartailler, Jürgen Reingruber
Cellular responses often require the fast activation or repression of specific genes, which depends on transcription factors (TFs) that have to quickly find the promoters of these genes within a large genome. TFs search for their DNA promoter target by alternating between bulk diffusion and sliding along the DNA, a mechanism known as facilitated diffusion. We study a facilitated diffusion framework with switching between three search modes: a bulk mode and two sliding modes triggered by conformational changes between two protein conformations...
July 2015: Physical Biology
Somenath Bakshi, Heejun Choi, James C Weisshaar
Single-molecule fluorescence provides high resolution spatial distributions of ribosomes and RNA polymerase (RNAP) in live, rapidly growing Escherichia coli. Ribosomes are more strongly segregated from the nucleoids (chromosomal DNA) than previous widefield fluorescence studies suggested. While most transcription may be co-translational, the evidence indicates that most translation occurs on free mRNA copies that have diffused from the nucleoids to a ribosome-rich region. Analysis of time-resolved images of the nucleoid spatial distribution after treatment with the transcription-halting drug rifampicin and the translation-halting drug chloramphenicol shows that both drugs cause nucleoid contraction on the 0-3 min timescale...
2015: Frontiers in Microbiology
Maximilian Bauer, Emil S Rasmussen, Michael A Lomholt, Ralf Metzler
Recent experiments show that transcription factors (TFs) indeed use the facilitated diffusion mechanism to locate their target sequences on DNA in living bacteria cells: TFs alternate between sliding motion along DNA and relocation events through the cytoplasm. From simulations and theoretical analysis we study the TF-sliding motion for a large section of the DNA-sequence of a common E. coli strain, based on the two-state TF-model with a fast-sliding search state and a recognition state enabling target detection...
2015: Scientific Reports
Davide Normanno, Lydia Boudarène, Claire Dugast-Darzacq, Jiji Chen, Christian Richter, Florence Proux, Olivier Bénichou, Raphaël Voituriez, Xavier Darzacq, Maxime Dahan
Many cellular functions rely on DNA-binding proteins finding and associating to specific sites in the genome. Yet the mechanisms underlying the target search remain poorly understood, especially in the case of the highly organized mammalian cell nucleus. Using as a model Tet repressors (TetRs) searching for a multi-array locus, we quantitatively analyse the search process in human cells with single-molecule tracking and single-cell protein-DNA association measurements. We find that TetRs explore the nucleus and reach their target by 3D diffusion interspersed with transient interactions with non-cognate sites, consistent with the facilitated diffusion model...
2015: Nature Communications
Yogesh K Gupta, Siu-Hong Chan, Shuang-Yong Xu, Aneel K Aggarwal
Type III R-M enzymes were identified >40 years ago and yet there is no structural information on these multisubunit enzymes. Here we report the structure of a Type III R-M system, consisting of the entire EcoP15I complex (Mod2Res1) bound to DNA. The structure suggests how ATP hydrolysis is coupled to long-range diffusion of a helicase on DNA, and how a dimeric methyltransferase functions to methylate only one of the two DNA strands. We show that the EcoP15I motor domains are specifically adapted to bind double-stranded DNA and to facilitate DNA sliding via a novel 'Pin' domain...
2015: Nature Communications
Mauro Ravera, Elisabetta Gabano, Ilaria Zanellato, Ilaria Bonarrigo, Manuela Alessio, Fabio Arnesano, Angela Galliani, Giovanni Natile, Domenico Osella
A series of Pt(IV) anticancer prodrug candidates, having the equatorial arrangement of cisplatin and bearing two aliphatic carboxylato axial ligands, has been investigated to prove the relationship between lipophilicity, cellular accumulation, DNA platination and antiproliferative activity on the cisplatin-sensitive A2780 ovarian cancer cell line. Unlike cisplatin, no facilitated influx/efflux mechanism appears to operate in the case of the Pt(IV) complexes under investigation, thus indicating that they enter by passive diffusion...
September 2015: Journal of Inorganic Biochemistry
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