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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.
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 (ILLUSTRATION AVAILABLE ON REQUEST).
"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. |
