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Researchers Discover
New Gene Regulation Mechanism:
Messenger RNA "Cut and Run" scheme provides
rapid stress response
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Cold Spring Harbor, NY, Oct. 20 -- Researchers at
Cold Spring Harbor Laboratory have discovered a new kind of messenger
RNA molecule that is converted from non-protein coding status to
protein coding status in response to cellular stress such as viral
infection. The discovery reveals a "cut and run" mechanism
that is likely to control the expression of many genes in humans
and other organisms. A deeper understanding of this mechanism is
predicted to have broad implications for biology and biomedical research.
The
central dogma of molecular biology holds that the DNA of genes is "transcribed" into
messenger RNA and messenger RNA is "translated" into protein.
The regulation of transcription and translation ultimately determines
whether particular genes are switched on to produce protein, or switched
off. Once they are made, most messenger RNA molecules are exported
from the cell nucleus to the cytoplasm and are then used in the cytoplasm
as templates for the production of protein. |
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However, a few years ago, Cold Spring Harbor Laboratory scientists
led by Dr. David Spector noticed that under standard growth conditions,
a particular population of messenger RNA molecules lingered in the
nucleus indefinitely--in structures they call "nuclear speckles"--and
never reached the cytoplasm.
"
We thought that these messenger RNAs must be doing something interesting
by hanging around in the nucleus, but at the time we didn't have
a way of finding out what that might be," says Spector. "Why
would they be produced if they would never be used?"
Then one of Spector's graduate students developed a method for purifying
speckles. That allowed the researchers to identify not only the many
different protein components of speckles, but also the messenger
RNAs that are the basis of the new study, published in the October
21 issue of the journal Cell. The study--spearheaded by Cold Spring
Harbor Laboratory postdoctoral fellow Dr. Kannanganattu Prasanth--identified
the first such messenger RNA: one transcribed from a mouse gene called
mCAT2 that encodes a cell surface receptor.
"
The first clue came when we found that the mCAT2 gene encodes two
different kinds of messenger RNAs; the standard protein coding version
that's exported to the cytoplasm as usual, and an atypical version
that remains in the nucleus," says Spector. "But the big
clue came when we thought about what the mCAT2 receptor does and
why the mCAT2 gene would encode a messenger RNA that stays in the
nucleus."
The scientists learned from the work of others that the mCAT2 receptor
is involved in the production of nitric oxide, and that nitric oxide
production is stimulated by various stress conditions including wound
healing and viral infection.
"
That told us that when cells are stressed, maybe the atypical messenger
RNA is released from the nucleus, exported to the cytoplasm, and
translated into protein, thus circumventing the time-consuming process
of producing new messenger RNA and providing a rapid response to
viral infection or other stresses," says Spector. To test this
idea, the researchers mimicked the effect of viral infection by treating
cells with interferon.
Sure enough, they discovered that the atypical mCAT2 messenger RNA
in the nucleus was rapidly cleaved in response to interferon treatment,
and that the protein coding portion of the molecule was then quickly
exported to the cytoplasm and translated into protein (see illustration).
"
This 'cut and run' mechanism is a completely new paradigm of gene
regulation, so studying it will keep us busy for a while. But we
already suspect that there is going to be a large family of genes
regulated in this way," says Spector.
In addition to Spector, Prasanth, and their colleagues at Cold Spring
Harbor Laboratory, researchers at ISIS Pharmaceuticals (Carlsbad,
CA) were involved in the study, which was funded by the National
Institutes of Health (NIGMS, NCI) and the Louis Morin Charitable
Trust.
Contact information for researchers familiar with but not involved
in the study is available on request.
For more information, visit www.cshl.edu. |
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