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A versatile cis-acting inverter module for synthetic translational switches.

ABSTRACT: Artificial genetic switches have been designed and tuned individually in living cells. A method to directly invert an existing OFF switch to an ON switch should be highly convenient to construct complex circuits from well-characterized modules, but developing such a technique has remained a challenge. Here we present a cis-acting RNA module to invert the function of a synthetic translational OFF switch to an ON switch in mammalian cells. This inversion maintains the property of the parental switch in response to a particular input signal. In addition, we demonstrate simultaneous and specific expression control of both the OFF and ON switches. The module fits the criteria of universality and expands the versatility of mRNA-based information processing systems developed for artificially controlling mammalian cellular behaviour.

SUBMITTER: Endo K

PROVIDER: S-EPMC3778853 | biostudies-other | 2013

REPOSITORIES: biostudies-other

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A versatile cis-acting inverter module for synthetic translational switches.

Endo Kei K Hayashi Karin K Inoue Tan T Saito Hirohide H

Nature communications 20130101

Artificial genetic switches have been designed and tuned individually in living cells. A method to directly invert an existing OFF switch to an ON switch should be highly convenient to construct complex circuits from well-characterized modules, but developing such a technique has remained a challenge. Here we present a cis-acting RNA module to invert the function of a synthetic translational OFF switch to an ON switch in mammalian cells. This inversion maintains the property of the parental swit ...[more]

PMID: 23999119

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Project description:BackgroundThe eukaryotic parasite Plasmodium falciparum causes millions of malarial infections annually while drug resistance to common anti-malarials is further confounding eradication efforts. Translation is an attractive therapeutic target that will benefit from a deeper mechanistic understanding. As the rate limiting step of translation, initiation is a primary driver of translational efficiency. It is a complex process regulated by both cis and trans acting factors, providing numerous potential targets. Relative to model organisms and humans, P. falciparum mRNAs feature unusual 5' untranslated regions suggesting cis-acting sequence complexity in this parasite may act to tune levels of protein synthesis through their effects on translational efficiency.MethodsHere, in vitro translation is deployed to compare the role of cis-acting regulatory sequences in P. falciparum and humans. Using parasite mRNAs with high or low translational efficiency, the presence, position, and termination status of upstream "AUG"s, in addition to the base composition of the 5' untranslated regions, were characterized.ResultsThe density of upstream "AUG"s differed significantly among the most and least efficiently translated genes in P. falciparum, as did the average "GC" content of the 5' untranslated regions. Using exemplars from highly translated and poorly translated mRNAs, multiple putative upstream elements were interrogated for impact on translational efficiency. Upstream "AUG"s were found to repress translation to varying degrees, depending on their position and context, while combinations of upstream "AUG"s had non-additive effects. The base composition of the 5' untranslated regions also impacted translation, but to a lesser degree. Surprisingly, the effects of cis-acting sequences were remarkably conserved between P. falciparum and humans.ConclusionsWhile translational regulation is inherently complex, this work contributes toward a more comprehensive understanding of parasite and human translational regulation by examining the impact of discrete cis-acting features, acting alone or in context.

Dataset Information

A versatile cis-acting inverter module for synthetic translational switches.

Publications

A versatile cis-acting inverter module for synthetic translational switches.

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