Gene-transcription Machinery Seen Poised For Action, Held In Check
Until Needed
Updated: 7/25/2007 5:11:57 PM
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Science Daily — For some time, scientists have been tracking down the
sequence of biochemical steps required to attract and assemble at the
head end of a gene the molecular machinery needed to transcribe that
gene to put to work the information it encodes. Now, a new study led
by researchers at The Wistar Institute suggests that the gene-
transcription machinery, once in place, can remain poised for action
but held in check until a triggering signal sends it on its way down
the linear DNA molecule.
The data outline a mechanism by which sets of critical genes could be
prepared for nearly instantaneous activation in response to stress or
other vital needs. Embryonic stem cells, for example, are known to
have numbers of genes held in this state of readiness.
In their investigations, the scientists were able to identify a
single molecule called ubiquitin that, when in place, appears to be
able to pause the transcription process after the needed machinery
has been assembled. Once that molecule is removed, the machinery --
with a molecule known as RNA polymerase II at its core -- is released
and transcription is set into motion. The research was done in yeast,
an often-used model organism for genetic studies. A report on the
findings appears in the current issue of Molecular Cell.
"In our experiments, we saw polymerase loaded onto the gene, but not
correctly activated," says Shelley L. Berger, Ph.D., the Hilary
Koprowski Professor at The Wistar Institute and senior author on the
study. "At the appropriate time, ubiquitin is removed, and this
triggers polymerase action. Data from other laboratories indicate
that stem cells have many genes that may be poised in this way, ready
to send the cells down various differentiation pathways to form
different tissues. There are likely many vital cell functions that
depend on a quick response which could be regulated by this process."
In earlier work, Berger and her coworkers looked at ways in which the
addition and removal of a small protein called ubiquitin modified
particular histones to regulate gene expression. Histones are
molecular structures around which DNA is tightly spooled as part of
the cell's scheme for maintaining order in the genome and securely
storing away genes until needed. Eight histones comprise a
nucleosome, and long strings of nucleosomes coil in turn into
chromatin, the basic material of chromosomes. Specific modifications
to histones have been associated with either gene repression or
activation. A key finding in the earlier study was that both the
addition and removal of ubiquitin at different times was required to
optimal transcription.
In the current study, experimental techniques were used to block the
removal of ubiquitin in order to illuminate the importance of the
removal step and detail the resulting effects.
"When ubiquitin cannot be removed from the histone, the first thing
seen is that a particular enzyme normally recruited into the process
at the start of productive gene expression could not get in," says
Anastasia Wyce, lead author on the Molecular Cell study. "The
machinery incorporating polymerase is assembled at the beginning of
the gene, but is not properly activated. Ubiquitin seems to serve as
something like a checkpoint until it is removed, at which point
polymerase is fully functional."
In addition to lead author Wyce and senior author Berger, the other
co-authors based at The Wistar Institute include Kelly A. Whelan,
Christine Kosman, and Wendy Walter. Wyce and Kosman also have
affiliations with the University of Pennsylvania. Tiaojiang Xiao and
Brian D. Strahl are with the University of North Carolina, Chapel
Hill; Dirk Eick is at the GSF-National Research Center for
Environment and Health, Munich; Timothy R. Hughes is associated with
the University of Toronto; and Nevan J. Krogan is with the University
of California, San Francisco.
The research was supported by the National Institutes of Health, the
National Science Foundation, and the Commonwealth Universal Research
Enhancement Program of the Pennsylvania Department of Health. Co-
author Strahl is a Pew Scholar in the Biomedical Sciences.
Note: This story has been adapted from a news release issued by The
Wistar Institute.
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StemCells subscribers may also be interested in these sites:
Children's Neurobiological Solutions
http://www.CNSfoundation.org/
Cord Blood Registry
http://www.CordBlood.com/at.cgi?a=150123
The CNS Healing Group
http://groups.yahoo.com/group/CNS_Healing
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