Puro design inteligente: como os precursores de pequenos RNAs reguladores de gene são escolhidos pela maquinaria celular

How Precursors of Gene-Regulating Small RNAs Are Sorted by Cellular Machinery

ScienceDaily (Jan. 5, 2010) — A team of scientists at Cold Spring Harbor Laboratory (CSHL) has determined a hierarchical set of criteria that explain how the molecular precursors of gene-regulating small RNAs are sorted by the cellular machinery.

Led by Benjamin Czech, a group working in the laboratory of CSHL Professor Gregory Hannon posed the question: can distinct patterns be observed in the process that unfolds when double-stranded RNAs enter the RNAi pathway? Shorthand for RNA interference, RNAi is a biological response to double-stranded RNA that can culminate in the regulation of gene expression. It has been observed in a vast range of organisms ranging from plants to worms to flies to man.

An enzyme called Dicer cuts double-stranded RNAs into smaller double-stranded pieces called duplexes. Czech, Hannon and colleagues propose rules governing the next step in the RNAi pathway, in which duplexes are sorted to proteins called Argonautes which are at the core of a molecular complex called RISC (the RNA-Induced Silencing Complex).

"Only one strand of each duplex is chosen," explains Czech, "and which one makes all the difference. In the fruit flies that we used as models for this series of experiments, the selection of one or another strand effectively determines whether the short RNA will seek out and regulate a gene, or whether it will perform another function such as protecting a cell against a viral invader."
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Molecular Cell
Volume 36, Issue 3, 13 November 2009, Pages 445-456

Hierarchical Rules for Argonaute Loading in Drosophila

1 Watson School of Biological Sciences, Howard Hughes Medical Institute, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA

2 Department of Genetics, Howard Hughes Medical Institute, Harvard Medical School, Boston, MA 02115, USA

Received 21 July 2009; revised 20 August 2009; accepted 28 August 2009. Published: November 12, 2009. Available online 12 November 2009.

Summary

Drosophila Argonaute-1 and Argonaute-2 differ in function and small RNA content. AGO2 binds to siRNAs, whereas AGO1 is almost exclusively occupied by microRNAs. MicroRNA duplexes are intrinsically asymmetric, with one strand, the miR strand, preferentially entering AGO1 to recognize and regulate the expression of target mRNAs. The other strand, miR*, has been viewed as a byproduct of microRNA biogenesis. Here, we show that miR*s are often loaded as functional species into AGO2. This indicates that each microRNA precursor can potentially produce two mature small RNA strands that are differentially sorted within the RNAi pathway. miR* biogenesis depends upon the canonical microRNA pathway, but loading into AGO2 is mediated by factors traditionally dedicated to siRNAs. By inferring and validating hierarchical rules that predict differential AGO loading, we find that intrinsic determinants, including structural and thermodynamic properties of the processed duplex, regulate the fate of each RNA strand within the RNAi pathway.

Author Keywords: RNA; PROTEINS

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