10th Conference on Retroviruses and Opportunistic Infections Boston, MA USA - February 10 -14, 2003

Conf Retroviruses Opportunistic Infect 2003 Feb 10-14;10th: abstract no. 49
Zamora P; Univ of Massachusetts Med Sch, Worcester

BACKGROUND: Double-stranded RNA can now be used in a wide variety of eukaryotes to suppress the expression of any gene, allowing rapid analysis of that gene's function, a technique known as RNA interference (RNAi). How cells use the information in double-stranded RNA to suppress gene expression and why they contain the machinery to do so remain subjects of intense scrutiny. The RNAi machinery harnesses the specificity of nucleic acids to direct effector proteins to down-regulate the expression of a specific gene. RNAi is unique in that almost any nucleic acid sequence can serve as a guide. Unlike anti-sense or ribozyme technology, RNAi exploits a bona fide cellular process to silence gene expression. The RNAi pathway appears to have originated as a defense against molecular parasites such as transposons and viruses, but in metazoans has taken on a broader range of functions, including eliminating abundant but defective messenger RNAs, regulating the production of developmentally important proteins, and triggering the formation of heterochromatin.

RESULTS: The double-stranded RNA-specific endonuclease, Dicer, produces 2 classes of functionally distinct small RNAs: microRNAs (miRNAs) and small interfering RNAs (siRNAs). In animals, miRNAs are thought to regulate mRNA translation, whereas siRNAs direct RNA destruction via the RNA interference (RNAi) pathway. Despite this apparent segregation of function, in cultured human cells the miRNA let-7 naturally enters the RNAi pathway, suggesting that the degree of complementarity between a miRNA and its RNA target is the sole determinant of small RNA function. Each let-7-containing RNA-protein complex catalyzes multiple rounds of RNA cleavage, explaining the remarkable efficiency of the RNAi pathway in human cells.

CONCLUSIONS: Current evidence suggests that RNA interference and other "RNA silencing" phenomena use a common cellular apparatus. The RNAi machinery is perhaps best viewed as an adapter complex that uses a small RNA guide to constrain a variety of effector functions (RNA cleavage, translational repression, chromatin remodeling) to a specific sequence of RNA or DNA. Because this complex can be reprogrammed to target virtually any sequence -- including both disease gene and viral sequences -- RNAi holds great promise as both an investigational tool and as a human therapeutic.

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Copyright © 2003 - Foundation for Retrovirology and Human Health. Reproduction of this abstract (other than one copy for personal reference) must be cleared through the Foundation for Retrovirology and Human Health. Licensed (AIDSLINE) from National Library of Medicine.