From: Damien Broderick (d.broderick@english.unimelb.edu.au)
Date: Sat Sep 22 2001 - 21:13:41 MDT
June 15, 2001; University of Texas Southwestern Medical Center; Dallas, TX
--
A discovery by UT Southwestern Medical Center at Dallas scientists that genes
near human telomeres can be silenced may help explain how and why humans age.
Telomeres are repeating sequences of DNA located at the end of each
chromosome
and are believed to function as a counting mechanism for cellular aging.
Dr. Jerry
Shay and Dr. Woodring Wright, UT Southwestern professors of cell biology,
report
in today's issue of Science that human cells can exhibit Telomere Position
Effect
(TPE), a mechanism by which genes near telomeres can be turned off, and
that the
strength of gene silencing is proportional to the length of nearby
telomeres. Shay and
Wright, along with collaborators at UT Southwestern, have previously shown
that
human cells age each time they divide because their telomeres shorten.
After a finite
number of cell divisions -- when telomeres become short -- the cells stop
dividing.
Most normal cells lack the enzyme telomerase, which maintains telomeres.
Telomerase is activated in 90 percent of all cancers, in which cells
continue to divide
at a high rate. Many diseases, including Down Syndrome, are characterized by
premature aging. Further understanding of TPE could help researchers
discover how
cellular aging contributes to the overall aging process. "This is an
important step in
trying to explain the connection between telomere shortening and aging,"
Shay said.
"Normal cells will only grow for a limited time. They grow for a while, and
then they
go through a process called senescence, or aging. We wanted to know about the
molecular memory. Are cells counting how many times they divide? We believe
the
telomeres are the molecular memory."
The researchers incorporated a piece of DNA containing a luciferase (the
enzyme
that allows fireflies to emit light) gene into human cells and showed that
if it became
located at the telomere, there was ten times less luciferase activity than
if it was
located in the middle of a chromosome. They also found an even greater
decrease
in luciferase activity if they used telomerase to make the telomeres grow
longer.
"We knew that when telomeres became too short, they caused cells to stop
dividing,
but there wasn't a mechanism for how a cell could sense how long its
telomeres were
before they became too short. TPE can do that. It can let a cell know how
old it is, so
that it could change its behavior before it became senescent," Wright said.
TPE could
help explain the differences between young and old cells. For example, if
there were
"aging" genes next to telomeres, they would be silent when the cells were
young. As
the cells aged and continued to divide, their telomeres would shorten; the
silencing of
the genes would be reversed; and the "aging" genes activated.
The researchers are now looking for naturally occurring human genes located
near telomeres
whose expression is influenced by telomere length. Joseph A. Baur, a UT
Southwestern
student research assistant in cell biology, and Dr. Ying Zou, a UT
Southwestern cell biology
Fellow, also were involved in the research. Shay and Wright's earlier
research has shown
that telomerase causes human cells grown in the laboratory to retain their
"youth" and
continue to divide long past the time when they normally would have stopped
dividing.
This discovery is making the use of normal cells for tissue engineering and
other
therapeutic uses much easier.
The investigators' Web site can be found at
http://www.swmed.edu/home_pages/cellbio/shay-wright.
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