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In mammals, there are six dedicated telomerespecific proteins: Telomeric Repeat Binding
Factor 1 (TRF1), Telomeric Repeat Binding Factor 2 (TRF2), TRF2 Interacting Protein (RAP1),
Adrenocortal Dysplasia Protein Homolog (TPP1), TRF1 Interacting Nuclear Factor 2 (TIN2),
and Protection of Telomeres 1 (POT1). Collectively, these are the shelterin complex. TRF1
and TRF2 bind directly to the telomere double strand, while POT1 binds to the single
stranded telomeric overhang and protects the 3 G-tail. TPP1 forms a complex with POT1
while binding with ssDNA, and may also be involved in recruiting telomerase. TIN2 links
ssDNA and dsDNA binding complexes, most probably at the d-loop formation. RAP1 is the
most conserved subunit of the shelterin complex, which binds to TRF2 and also acts as a
transcription regulator. TRF1 and TRF2 bear similar domains recognizing TTAGGG domain on
dsDNA of the telomere and has a docking motif TRFH (TRF homology) that dimerizes either
TRF1 or TRF2.
This shelterin complex is located at the end of every telomere and helps stabilize the
isolated secondary structure of the DNA at the G-tail, while preventing recognition by DDR.
As such, the shelterin complex envelops chromosome ends from DNA damage-sensing and
repair pathways. It also regulates post-replication restoration of telomeric DNA and acts as a
platform for DNA replication, recombination, and remodeling of the chromatin.
Another protein complex called CST contains 4 subunits: DNA polymerase , two primase
accessory factors CTC1 (CST telomere maintenance complex component 1) and STN1
(suppressor of cdc thirteen 1), and TEN1 (telomeric pathways with STN1). The CST complex
has been found to associate with only a subset of the telomeres. While research is still being
conducted, the CST complex is probably involved in limiting overhang length and in the
synthesis of the telomeres C-strand (complimentary to the G-tail), and in cell replication by
releasing stalled replication forks.
The telomere nucleoprotein complex has a third non-coding RNA component called TERRA
(telomeric-repeat-containing RNA) and is thought to act as a direct telomerase inhibitor and
important for telomere maintenance and function. TRF2, via its G-quadruplex structure (G4),
binds TERRA, believed to introduce another level of regulation. TERRA forms an integral part
of telomere heterochromatin and is involved in the state of telomeric chromatin as the cell
develops and differentiates. Transcription of TERRA occurs at almost all chromosome ends
and occurs in response to telomere length. TERRA expression varies during the cell cycle,
with a low level in the late S phase and a high level in early to mid G1 phase. Some studies
have found interference with telomere replication as TERRA accumulates.
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Conclusion
The study of telomere biology has enhanced our knowledge of the origin of
cancer and has given us possible avenues to explore for inhibiting its progression.
However, these studies are far from complete! Every possible tactic has its pluses,
minus and unknown side reactions. Studies have shown that the enzyme
telomerase is a key player in cell proliferation and that its activity is increased by
85% in human cancers (3). Therefore, the inhibition of telomerase activity seems to
be a likely option for a therapeutic strategy; however, four potential problems arise.
First, in the absence of telomerase, the telomeres become too short for DNA
polymerase to duplicate the ends of the chromosomes. The telomere depleted
chromosomes then trigger a DNA-damage response which usually results in
senescence. Even though the cells may not be dividing any longer, they may secret
a toxin that causes inflammation which later may result in cancer (3). Secondly, the
cancer cells could bypass regulatory mechanisms via ALT pathways and facilitate
the growth of cancer! Thirdly, there is the uncertainty that all cancers will react the
same way to the telomerase inhibitor, plus, there could be unforeseen side affects.
And lastly, there is the issue of how to administer the inhibitor to just the targeted
cells. If the cancer formed due to a depletion of the telomere, then, the healthy
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cells with telomerase activity may survive. Conversely, what if the cancer was
caused by the telomeres being too long, then this approach would be irrelevant.
Another possible therapeutic strategy would be to disrupt the function of the
telomere itself. Even though this approach may be quicker then waiting for the
telomere to shorten, this method faces similar dilemmas as with using a telomerase
inhibitor; such as, toxicity, the possible use of ALT pathways and targeting
administration. The telomere-disrupting agents would not be able to distinguish
between healthy and cancerous cells; therefore, the survival of normal cells would
be affected as well.
A third option discussed was the hopeful strategy with the use of telomerasetargeted immunotherapy. Cytotoxic T lymphocytes (CTL) can recognize antigens
and TERT determinants on the surface of cancer cells and destroy them; however,
this method cant be used to target all types of cancer. The tumor must express a
tumor antigen or telomerase in order for CTL to recognize it, plus, a wide range of
antigens would be needed to target different cancers.
The last therapeutic option mentioned was the use of oncolytic viruses which
prohibits the replication of TERT-positive cells. Not only does this method have
concerns with the survival of healthy cells, but a better understanding of whether or
not TERT has other cellular functions besides telomere lengthening is required.
Unknown adverse effects may be associated with the disruption of TERT.
Telomere biology is important to ensure genome stability; however,
encouraging telomere dysfunction may inhibit the formation of cancer. Before a
cure for cancer can be discovered, continued research is most definitely required for
a more comprehensive understanding of telomere biology.
Bibliography
1. "Ataxia-telangiectasia." Genetics Home Reference. 2 Mar 2015. U.S. National
Library of Medicine. 3 Mar. 2015. <http://ghr.nlm.nih.gov/condition/ataxiatelangiectasia>.
2. Berg, Jeremy M., John L. Tymoczko, and Lubert Stryer. Biochemistry, Seventh
Edition. New York: W.H. Freeman and Company, 2012. pg. 819-846.
3. Xu, Lifeng, Shang, Li, and Bradley A. Stohr. "The Role of Telomere Biology in
Cancer." Annual Review of Pathology: Mechanisms of Disease. Annual
Reviews, 28 Aug. 2012. Web. 14 Feb. 2015. <pathol.annualreviews.org>.
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