miRNA Target for Treating Hepatitis C

Scientists from the Southwest Foundation for Biomedical Research, Santaris Pharma, and Aalborg University may have found a miRNA target for treating hepatitis C. In work appearing in Science Express this week, they show that in chimps infected with hepatitis C virus, injecting a locked nucleic acid complementary to miR-122 “leads to long-lasting suppression of HCV viremia with no evidence for viral resistance or side effects in the treated animals.” HCV needs miR-122 in order to accumulate; by turning this miRNA off, according to transcriptome analysis, they saw that genes targeted by miR-122 were turned back on and interferon-regulated genes were down-regulated.

Two studies in this week’s issue look at the structures of proteins involved in translocation and translation. In the first, scientists led by Roland Beckmann at LMU Munich and the University of Massachusetts Medical School’s Elisabet Mandon combined cryo-electron microscopy and biochemical data to find that the Sec61/SecY complex, which serves as a channel for membrane and secretory proteins during protein translation, acts alone as a monomer, and that the growing peptide occupies the complex’s central pore.

In another, Beckmann led a group that used cryo-electron microscopy to visualize the ribosome stalled during translation of the TnaC leader peptide, which is upstream of the E. coli tryptophanase operon. At 5.8 angstroms, the nascent peptide chain had a distinct conformation within the ribosome exit tunnel that led to stalling of translation. A perspective adds insight.

In more structural work, researchers led by Elizabeth Getzoff at the Scripps Institute report the structure of pyrabactin resistance 1 (PYR1), a component of the abscisic acid receptor protein that functions in early ABA signaling. The phytohormone ABA is important in seed dormancy and protecting plants against environmental stresses like drought. “Small-angle x-ray scattering suggests that ABA signals by converting PYR1 to a more compact, symmetric closed-lid dimer,” they write. A related perspective talks more about seeds and their contribution to a plant’s survival.

This week, Science announced the GE Prize Essay winner, Michael Crickmore. His essay touches on how genetic programs determine whether an animal will be big or small. “Although we know that Hox transcription factors specify the identity of individual fingers, toes, and ribs, little is known about how their individual sizes are programmed,” he writes. Crickmore did his graduate work on size at Columbia University and is now doing a postdoc with Leslie Vosshall at Rockefeller University studying how the brain works.

RNAi Interference Video

http://www.dnatube.com

RNA interference (also called “RNA-mediated interference”, abbreviated RNAi) is a mechanism for RNA-guided regulation of gene expression in which double-stranded ribonucleic acid inhibits the expression of genes with complementary nucleotide sequences. Conserved in most eukaryotic organisms, the RNAi pathway is thought to have evolved as a form of innate immunity against viruses and also plays a major role in regulating development and genome maintenance.

The RNAi pathway is initiated by the enzyme dicer, which cleaves double-stranded RNA (dsRNA) to short double-stranded fragments of 20–25 base pairs. One of the two strands of each fragment, known as the guide strand, is then incorporated into the RNA-induced silencing complex (RISC) and base-pairs with complementary sequences. The most well-studied outcome of this recognition event is a form of post-transcriptional gene silencing. This occurs when the guide strand base pairs with a messenger RNA (mRNA) molecule and induces degradation of the mRNA by argonaute, the catalytic component of the RISC complex. The short RNA fragments are known as small interfering RNA (siRNA) when they derive from exogenous sources and microRNA (miRNA) when they are produced from RNA-coding genes in the cell’s own genome. The RNAi pathway has been particularly well-studied in certain model organisms such as the nematode worm Caenorhabditis elegans, the fruit fly Drosophila melanogaster, and the flowering plant Arabidopsis thaliana.

The selective and robust effect of RNAi on gene expression makes it a valuable research tool, both in cell culture and in living organisms; synthetic dsRNA introduced into cells can induce suppression of specific genes of interest. RNAi may also be used for large-scale screens that systematically shut down each gene in the cell, which can help identify the components necessary for a particular cellular process or an event such as cell division. Exploitation of the pathway is also a promising tool in biotechnology and medicine.

Historically, RNA interference was known by other names, including post transcriptional gene silencing, transgene silencing, and quelling. Only after these apparently-unrelated processes were fully understood did it become clear that they all described the RNAi phenomenon. RNAi has also been confused with antisense suppression of gene expression, which does not act catalytically to degrade mRNA but instead involves single-stranded RNA fragments physically binding to mRNA and blocking translation. In 2006, Andrew Fire and Craig C. Mello shared the Nobel Prize in Physiology or Medicine for their work on RNA interference in the nematode worm C. elegans,[4] which they published in 1998


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