HOW THE ENDS OF CHROMOSOMES ARE MAINTAINED FOR CANCER CELL IMMORTALITY
Maintaining the ends
of chromosomes, called telomeres, is a requisite feature of cells that are able
to continuously divide and also a hallmark of human cancer. "Telomeres are
much like the plastic cap on the ends of shoelaces -- they keep the ends of DNA
from fraying," says Roger Greenberg, MD, PhD, associate professor of
Cancer Biology in the Perelman School of Medicine at the University of
Pennsylvania. In a new study published this week in Cell, he
and his colleagues describe a mechanism for how cancer cells take over one of
the processes for telomere maintenance to gain an infinite lifespan
Telomeres stay intact
in most cancer cell types by means of a specialized enzyme called telomerase
that adds the repetitive telomere DNA sequences to the ends of chromosomes.
Cancer cells can also use a second method involving a DNA-repair-based
mechanism, called alternative lengthening of telomeres, or ALT for short. In
general, cancer cells take over either type of telomere maintenance machinery
to become immortal. Overall, approximately fifteen percent of cancers use the
ALT process for telomere lengthening, but some cancer types use ALT up to 40 to
50 percent of the time.
Greenberg's co-authors
of the new findings are Nam Woo Cho and Robert L. Dilley, both MD/PhD students
in his lab, and Michael A. Lampson, an associate professor of Biology at Penn.
Greenberg is also an associate investigator at the Abramson Family Cancer Research
Institute and director of Basic Science for the Basser Research Center for
BRCA.
Going Fishing The team
showed that when DNA breaks, it triggers DNA repair proteins like the breast
cancer suppressor protein BRCA2 into action, along with other helper proteins,
that attach to the damaged stretch of DNA. These proteins stretch out the DNA,
allowing it to search for complementary sequences of telomere DNA. Breast
cancer is linked to mutations in the BRCA1 and BRCA2 genes and mutations in
several genes involved in BRCA-related pathways have also been associated with
breast cancer susceptibility. Breast and ovarian cancers are associated with a
breakdown in the DNA repair systems involving these BRCA and other related
proteins.
"This process of
repair triggers the movement and clustering of telomeres like fish being reeled
toward an angler," explains Greenberg. "The broken telomeres use a
telomere on a different chromosome -- the homologous telomere -- as a template
for repair." In fact, in cancer cells that use ALT to maintain their
telomeres, the team could visualize this process by imaging these clusters of
telomeres coming together.
"We are very
excited about the data as it has provided new insights into this mechanism of
telomere maintenance and ways to think about BRCA dependent and independent DNA
recombination," he says. "But, as with most scientific studies, many
more questions are raised than answers provided."
The team would like to
find other proteins involved in ALT and look for small molecule drugs that
target this telomere maintenance mechanism in cancer cells to selectively kill
cancer types that use ALT.
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