gene-silencing MicroRNAs update

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Molecular steps involved in the creation of gene-silencing MicroRNAs

identified

23 Jun 2005 Medical News Today

First discovered only a few brief years ago, microRNAs are small,

remarkably powerful molecules that appear to play a pivotal role in

gene silencing, one of the body's main strategies for regulating its

genome. A scant 22 nucleotides in length, miRNAs appear to work by

binding to and somehow interfering with messenger RNA, itself

responsible for translating genes into proteins.

But how do miRNAs arise? And what can we learn about their biological

function from their origins? In a study published last year in

Nature, researchers at The Wistar Institute identified a two-protein

complex, called the microprocessor complex, which controls the

earliest steps in the creation of miRNAs in the cell nucleus.

Now, in a new study published online by Nature today, the Wistar

group has identified a three-protein complex that picks up the

process in the cell cytoplasm and carries it through to the

maturation of the finished miRNAs.

Taken together, the two Nature studies trace the generation of miRNAs

from the genes that give rise to long primary RNA molecules through

to the mature miRNAs that target messenger RNA. Significantly, the

research also shows that the finished miRNAs are associated with a

protein called Argonaute 2, known to be involved in inactivating

messenger RNA.

" In this study, we were able to link processing of the miRNAs

directly through to the molecules responsible for silencing genes, "

says Ramin Shiekhattar, Ph.D., an associate professor at Wistar and

senior author on both Nature studies. " The miRNAs provide specificity

for those molecules, which do the actual work of gene silencing. "

Intriguingly, the research also links the process of creating miRNAs

with aspects of the HIV life cycle and with tumor suppression. The

study identifies three proteins that work together in the cytoplasm

to create finished miRNAs. Individually, each of the proteins was

known previously, but their joint role in producing miRNAs is newly

delineated here. Equally as important, however, is the fact that

while two of the proteins had been associated with miRNAs in earlier

work, the third protein, TRBP, had not been. And TRBP is clearly a

protein of interest to scientists.

" TRBP was first observed as a protein that binds to HIV during

transcription of the virus, " says Shiekhattar. " The tantalizing

implication is that the RNA interference pathway may play a

significant role in HIV replication. TRBP has also been identified as

a tumor suppressor, which suggests still other connections to be

explored. "

The lead authors on the Nature study are Thimmaiah Chendrimada,

I. , and Easwari Kumaraswamy, with each contributing

equally to the work. The remaining co-authors are Norman,

Neil Cooch, and Wistar professor Kazuko Nishikura, Ph.D.

Corresponding author Shiekhattar is an associate professor in two

programs at Wistar, the gene expression and regulation program and

molecular and cellular oncogenesis program. Support for the research

was provided by the National Institutes of Health, the American

Cancer Society, and the Jane Coffin Child Memorial Fund for Medical

Research.