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Senior Citizen Health & Medicine
Cancer Links to Aging Painted on Palette by Salk
Researchers
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The chromosomes
were isolated from a cell taken from a patient with Werner
Syndrome, a premature aging disease that is caused by the loss
of the WRN gene. Painting each chromosome pair in a different
color reveals the breakage and fusion of chromosomes (see
chromosomes 6 and 10), which causes genomic instability and
could explain the high incidence of cancer among individuals
with Werner syndrome. |
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Predicts cancer in older people has same basis as
that in Werner Syndrome patients
Feb. 6, 2007 - Wielding a palette of chromosome paints,
scientists at the Salk Institute for Biological Studies have taken a
step closer to understanding the relationship between aging and cancer
by visualizing chromosomes of cells from patients with a heritable
premature aging disease known as Werner Syndrome.
In a study to be published in this week’s online
edition of the Proceedings of the National Academy of Sciences
researchers led by Jan Karlseder, Ph.D., assistant professor in Salk’s
Regulatory Biology Laboratory, showed that rebuilding structures called
telomeres, which are found at the tips of each chromosome, significantly
blocks the type of genetic damage seen in cells of patients with Werner
Syndrome.
Patients with Werner Syndrome manifest signs of
aging, such as skin wrinkling, baldness, or hair graying, in their
teens. Most die in their 40’s or 50’s due to a predisposition to
diseases like cancer.
“Cancer is almost always related to chromosomal
instability,” explains Karlseder. “If telomeres are lost on individual
chromosomes, then chromosomes are not protected and can fuse with other
nonprotected chromosomes. Then when cells divide, chromosomes randomly
break, leading to genome instability.”
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The current study extended work published in 2004
by Karlseder and first author Laure Crabbe, Ph.D., who was a graduate
student in the Karlseder lab at the time. In that work, the team used a
technique called FISH—short for fluorescent in situ hybridization—to
microscopically visualize both the telomeres and chromosomal DNA from
Werner Syndrome patients.
They reported that some protective telomeres were
actually missing on patients’ chromosomes, a finding Karlseder describes
as “a fairly catastrophic event for a cell.”
For the current study, Salk researchers grew cells
from Werner Syndrome patients in tissue culture dishes and, aided by
colleagues at the Institute of Human Genetics in Heidelberg, Germany,
evaluated DNA damage using a highly colorful variation of the FISH
technique called chromosome painting.
This technique “paints” or labels every pair of the
46 chromosomes with a different colored fluorescent dye, enabling
investigators to easily see breakage or fusion of chromosomes that are
characteristic of damaged DNA under the microscope.
Then they artificially supplied the cultured cells
with one of two genes—either a functional copy of the WRN gene, which is
mutant or nonfunctional in Werner Syndrome, or a gene encoding the
protein telomerase, which elongates short or missing telomeres.
After cells divided several times, their DNA was
reexamined for the type of damage associated with both aging and cancer.
Cells supplied with a functional WRN gene showed
decreased DNA damage compared to untreated cells, which was predictable:
the WRN gene encodes a protein called a helicase that unwinds tightly
coiled DNA strands when cells divide.
Loss of WRN protein in individuals with Werner
Syndrome is responsible for the disease.
Explains Crabbe, now a postdoctoral fellow at The
Institute of Human Genetics in Montpellier, France, “The lack of a
single protein (WRN) induced loss of some telomeres, leading to a
premature cellular growth arrest.”
However, the most interesting finding was what the
scientists observed in cells supplied with added telomerase.
“When we put telomerase into cells, we suppressed
accumulation of mutations to the same degree as when we put the WRN
protein back,” reports Karlseder. “It fixed the defect by elongating
short telomeres seen in Werner Syndrome cells.”
Crabbe, who is continuing to study DNA replication
as a postdoc, concludes that these findings not only provide a mechanism
underlying accelerated aging seen in Werner Syndrome but establish a
link to cancer predisposition, saying, “These results indicate that the
telomere dysfunction in Werner Syndrome cells is a major cause of
genomic instability and could explain the high incidence of cancer seen
in this disease.”
Translating these findings into a treatment for
Werner Syndrome will be extremely difficult. However, Karlseder feels
optimistic about what these investigations show.
“We study this disease because it is an excellent
model for aging, and we show here a direct relation between aging,
telomere loss, and cancer occurrence,” he says.
“I predict that cancer in older people has
precisely the same basis as that seen in Werner Syndrome patients. That
is why this was such a satisfying study.”
Also contributing to this study were graduate
student Colleen Naeger in the Karlseder lab and Anna Jauch, Ph.D., and
Heidi Holgreve-Grez, Ph.D., in Heidelberg.
The Salk Institute for Biological Studies in La
Jolla, California is an independent nonprofit organization dedicated to
fundamental discoveries in the life sciences, the improvement of human
health, and the training of future generations of researchers. Jonas
Salk, M.D., whose polio vaccine all but eradicated the crippling disease
poliomyelitis in 1955, opened the Institute in 1965 with a gift of land
from the City of San Diego and the financial support of the March of
Dimes.
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