Twin molecular scissors link creation of microRNAs with gene-silencing

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Twin molecular scissors link creation of microRNAs with gene-silencing

http://www.medicalnewstoday.com/medicalnews.php?newsid=33234

One of the body's primary strategies for regulating its genome is a

kind of targeted gene silencing orchestrated by small molecules

called microRNAs, or miRNAs. First observed only a few years ago,

these molecules appear to inactivate messenger RNA, itself

responsible for translating genes into proteins. Scientists have been

eager to know more about miRNAs, clearly important players on the

genetic field despite having gone unnoticed for so long. How are they

produced? And how do they work?

In a series of studies published over the past year, a research team

at The Wistar Institute has provided considerable insight into the

world of miRNAs. In their first study, which appeared last year in

Nature, they identified a two-protein complex, called the

microprocessor, which controls the earliest steps in the creation of

miRNAs in the cell nucleus. In their next study, published in Nature

earlier this year, the Wistar group described a three-protein complex

that picks up the process in the cell cytoplasm and carries it

through to the maturation of the finished miRNAs.

Now, in new findings published online November 3 in Cell, Wistar

professor Ramin Shiekhattar, Ph.D., and his colleagues report that

the three-protein complex has been identified as RISC, a previously

glimpsed but ill-defined molecular complex known to be involved in

gene silencing. RISC, the new study demonstrates, not only oversees

production of miRNAs, as described in the earlier study this year,

but is also responsible for miRNA specificity in silencing particular

messenger RNAs.

In RISC, two of the three components, Dicer and Argonaute 2, are

enzymes bound together by the third member, TRBP. Dicer cuts double-

stranded precursor molecules shaped like hairpins into pairs of short

single-stranded miRNAs - in essence, nipping off the bend in the pin.

RISC then unzips the two single-stranded miRNAs from each other and

identifies and holds one as a guide to help it find the specific

messenger RNA to be inactivated. Using complementarity to match the

guide miRNA to a particular length of its target messenger RNA, Dicer

and TRBP then hand over the messenger RNA for cutting by Argonaute 2.

Still holding the guide miRNA, RISC then scouts for additional copies

of its target messenger RNA to cut. The cutting destroys the

messenger RNA, effectively silencing the gene from which it was

transcribed.

" The two enzymes in the complex are like two scissors working

together in a concerted fashion, connected and coordinated by the

third member of the complex, " Shiekhattar explains.

Another scientific question surrounding RISC was also resolved by the

current study. Some investigators had theorized that the activity of

RISC required ATP for energy. ATP, or adenosine triphosphate, is a

molecule used to store and release energy for tasks throughout the

body.

" The work of RISC is being accomplished with no energy requirement

whatsoever, " Shiekhattar says. " All of the activity - the separation

of the strands, the multiple cutting steps, everything - is being

done in the absence of any energy use. "

Instead, he says, the different molecules involved have stronger and

weaker affinities for each other that govern their stepwise

associations and disassociations as the process unfolds.

The lead author on the Cell study is I. . The co-

authors are Thimmaiah P. Chendrimada and Neil Cooch. Corresponding

author Shiekhattar is a 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 and the Jane Coffin Childs Memorial

Fund for Medical Research.