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The old and new RNA world

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Among the numerous hypotheses offering a scenario for the origin of life on Earth, the one called “The RNA World” has gained the most attention. According to this hypothesis RNA acted as a genetic information storage material, as a catalyst of all metabolic reactions, and as a regulator of all processes in the primordial world. Various experiments show that RNA molecules could have been synthesized abiotically, with the potential to mediate a whole repertoire of metabolic reactions. Ribozymes carrying out aminoacyl-tRNA reactions have been found in SELEX (systematic evolution of ligands by exponential enrichment) approaches and the development of a ribosome from a RNA-built protoribosome is easy to imagine. Transfer RNA aminoacylation, protoribosome origin, and the availability of amino acids on early Earth allowed the genetic code to evolve. Encoded proteins most likely stabilized RNA molecules and were able to create channels across membranes. In the modern cell, DNA replaced RNA as the main depositor of genetic information and proteins carry out almost all metabolic reactions. However, RNA is still playing versatile, crucial roles in the cell. Apart from its classical functions in the cell, a huge small RNA world is controlling gene expression, chromatin condensation, response to environmental cues, and protecting the cell against the invasion of various nucleic acids forms. Long non-coding RNAs act as crucial gene expression regulators. Riboswitches act at the level of transcription, splicing or translation and mediate feedback regulation on biosynthesis and transport of the ligand they sense. Alternative splicing generates genetic variability and increases the protein repertoire in response to developmental or environmental changes. All these regulatory functions are essential in shaping cell plasticity in the changing milieu. Recent discoveries of new, unexpected and important functions of RNA molecules support the hypothesis that we live in a New RNA World.
Although the delta ribozymes have been stud ied for more than ten years the most im- por tant in for ma tion con cern ing their struc ture and mech a nism of ca tal y sis were only ob tained very re cently. The crys tal struc ture of the genomic delta ribozyme turns out to be an ex cel lent ex am ple of the ex traor di nary prop er ties of RNA mol e cules to fold into uniquely com pact struc tures. De tails of the X-ray struc ture have greatly stim u- lated fur ther stud ies on the fold ing of the ribozymes into func tion ally ac tive mol e cules as well as on the mech a nism of RNA ca tal y sis. The abil ity of the delta ribozymes to carry out gen eral acid-base ca tal y sis by nu cle o tide side chains has been as sumed in two pro posed mech a nisms of self-cleavage. Re cently, con sid er able prog ress has been also made in char ac ter iz ing the cat a lytic prop er ties of trans-act ing ribozyme vari ants that are po ten tially at trac tive tools in the strat egy of di rected RNA degradation.
To downregulate expression of the β1 integrin subunit in endothelial cells, plasmid encoding the ribozyme cassette containing hammerhead ribozyme flanked at the 5' terminus by tRNAVal and at the 3' terminus by constitutive transport element sequences was constructed. When used to transfect immortalized human endothelial cell line EA.hy 926, it selectively blocked the synthesis of the β1 integrin subunit and thus inhibited migration and proliferation of the cells. Thus, this construct may be a valuable tool to control the proangiogenic phenotype of stimulated endothelial cells.
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