Transcription factor logic using chemical complementation

Bronson, Jonathan E.; Mazur, William W.; Cornish, Virginia W.

doi:10.1039/b713852k

Cited by 29 publications

(21 citation statements)

References 19 publications

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“…They have since modified this system to reduce potential MTX toxicity (but unfortunately losing some activity) by replacing it with the bacterial-specific DHFR inhibitor trimethoprim (45). Most recently, these latter two systems were combined to demonstrate their use as part of a five-input logic circuit (46). The output of the circuit ( lacZ transcription) is predictably controlled by the binary variables of presence/absence of unmodified MTX (which inhibits the system in high concentrations), dexamethasone-MTX, dexamethasone-trimethoprim, glucose, and galactose (since the GAL1 promoter that controls the transgene expression is active in the presence of galactose and repressed in the presence of glucose).…”

Section: Techniques Requiring Genetic Manipulationmentioning

confidence: 99%

Design and Applications of Bifunctional Small Molecules: Why Two Heads Are Better Than One

2008

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Induction of protein-protein interactions is a daunting challenge, but recent studies show promise for small molecules that specifically bring two or more protein molecules together for enhanced or novel biological effect. The first such bifunctional molecules were the rapamycin- and FK506-based “Chemical Inducers of Dimerization”, but the field has since expanded with new molecules and new applications in chemical genetics and cell biology. Examples include coumermycin-mediated gyrase B dimerization, proteolysis targeting chimeric molecules (PROTACS), drug hybrids, and strategies for exploiting multivalency in toxin binding and antibody recruitment. This review discusses these and other advances in the design and use of bifunctional small molecules, and potential strategies for future systems.

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Section: Techniques Requiring Genetic Manipulationmentioning

confidence: 99%

Design and Applications of Bifunctional Small Molecules: Why Two Heads Are Better Than One

2008

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“…(13)(14)(15)(16)(17) It is therefore worth analysing the explicit and implicit hypotheses made when the lactose operon is used as a theoretical or an experimental model. Interestingly, in a work combining in silico modelling with experiments, (15) an equation placed in the Supplementary Material of the corresponding article (which is the typical place where one finds authentic engineering constraints) shows that a leak or a degradative process is essential to permit realistic modelling of the multistability process in the lactose utilisation network.…”

Section: Introductionmentioning

confidence: 99%

Cells need safety valves

Danchin

2009

BioEssays

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In Escherichia coli, the role of lacA, the third gene of the lactose operon, has remained an enigma. I suggest that its role is the consequence of the need for cells to have safety valves that protect them from the osmotic effect created by their permeases. Safety valves allow them to cope with the buildup of osmotic pressure under accidental transient conditions. Multidrug resistance (MDR) efflux, thus named because of our anthropocentrism, is ubiquitous. Yet, the formation of simple leaks would result in futile influx/efflux cycles. Versatile modification enzymes with low sensitivity solve the problem if the modified metabolite is the one exported by MDR permeases. This may account for the pervasive presence of acetyltransferases, such as LacA, associated to acetylmetabolite exporters. This scenario of constraints imposed by efficient influx of metabolites provides us with a model that should be followed when constructing synthetic cells.

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“…To date, a number of synthetic gene circuits1112131415161718192021 have been constructed to perform various digital logic functions and have demonstrated the great potential of using biological computational circuits10222324 to customize cell signalling. However, most of these gene circuits are not modular (that is, they are limited by having to use specific inputs and outputs) or are not insulated from their host chassis (that is, they are limited by having to operate in a specific genetic background to avoid potential cross-talk or at the cost of affecting the host genetic machinery).…”

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confidence: 99%

Engineering modular and orthogonal genetic logic gates for robust digital-like synthetic biology

et al. 2011

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Modular and orthogonal genetic logic gates are essential for building robust biologically based digital devices to customize cell signalling in synthetic biology. Here we constructed an orthogonal AND gate in Escherichia coli using a novel hetero-regulation module from Pseudomonas syringae. The device comprises two co-activating genes hrpR and hrpS controlled by separate promoter inputs, and a σ54-dependent hrpL promoter driving the output. The hrpL promoter is activated only when both genes are expressed, generating digital-like AND integration behaviour. The AND gate is demonstrated to be modular by applying new regulated promoters to the inputs, and connecting the output to a NOT gate module to produce a combinatorial NAND gate. The circuits were assembled using a parts-based engineering approach of quantitative characterization, modelling, followed by construction and testing. The results show that new genetic logic devices can be engineered predictably from novel native orthogonal biological control elements using quantitatively in-context characterized parts.

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Transcription factor logic using chemical complementation

Abstract: Chemical complementation was used to make a transcription factor circuit capable of performing complex Boolean logic.

Cited by 29 publications

References 19 publications

Design and Applications of Bifunctional Small Molecules: Why Two Heads Are Better Than One

Design and Applications of Bifunctional Small Molecules: Why Two Heads Are Better Than One

Cells need safety valves

Engineering modular and orthogonal genetic logic gates for robust digital-like synthetic biology

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