Transcript Telomeres and Telomerase

Telomeres and Telomerase
the internal clock is ticking…
Normal DNA replication
• At the 5’ end, after RNA primer
comes off, the DNA
polymerase cannot fill in the
end
• The ends of DNA strands have
additional repeated sequences
of nucleotides (telomeres)
• Over many DNA replications,
these telomeres shorten until
the cell can no longer
replicate.
Without a telomere…
• Telemeres also can:
– Protect open ends of chromosomes from enzymatic digestion
– Anchor chromosomes to nuclear membrane (important for
chromosome transcription)
– Prevent clumping of chromosomes during anaphase
Without a telomere…
• Telemeres also can:
– Protect open ends of chromosomes from enzymatic digestion
– Anchor chromosomes to nuclear membrane (important for
chromosome transcription)
– Prevent clumping of chromosomes during anaphase
• Open ends of chromosomes are “sticky”; therefore, without
telemeres capping the ends, several linear chromosomes may clump
together.
Without a telomere…
• Telemeres also can:
– Protect open ends of chromosomes from enzymatic digestion
– Anchor chromosomes to nuclear membrane (important for
chromosome transcription)
– Prevent clumping of chromosomes during anaphase
• Open ends of chromosomes are “sticky”; therefore, without
telemeres capping the ends, several linear chromosomes may clump
together.
• All mammals have TTAGGG as the repeating telomere sequence
Without a telomere…
• Telemeres also can:
– Protect open ends of chromosomes from enzymatic digestion
– Anchor chromosomes to nuclear membrane (important for
chromosome transcription)
– Prevent clumping of chromosomes during anaphase
• Open ends of chromosomes are “sticky”; therefore, without
telemeres capping the ends, several linear chromosomes may clump
together.
• All mammals have TTAGGG as the repeating telomere sequence
• Other organisms may have TTGGGG as their sequence
Without a telomere…
• Telemeres also can:
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– Protect open ends of chromosomes from enzymatic digestion
– Anchor chromosomes to nuclear membrane (important for
chromosome transcription)
– Prevent clumping of chromosomes during anaphase
Open ends of chromosomes are “sticky”; therefore, without
telemeres capping the ends, several linear chromosomes may clump
together.
All mammals have TTAGGG as the repeating telomere sequence
Other organisms may have TTGGGG as their sequence
When telomeres shorten too far, it may either cause altered gene
expression or signal for apoptosis.
Telomeres and diseases
• Shortened telomeres may be the culprit to such diseases as:
– Diseases of premature aging
• Down’s Syndrome
• Hutchinson-Gilford progeria
• Werner syndrome
• People with these diseases have demonstrated either short
telomeres or accelerated telomere shortening.
– May also be cause of
• Degenerative joint disease
• Sensory impairment
– Many cancers take advantage of telomeres too
Telomerase
• Consists of at least 3
components
– Telomerase reverse
transcriptase (TERT)
– Telomerase-associated protein
1 (TEP1) – regulatory function
(? not known for sure)
– Telomerase RNA subunit
• telomerase in action
Telomerase
Telomerase and cancer cells
• Active telomerase found in 90% of human tumors.
• Telomerase does NOT cause cancer; it only allows cancer cells to
continue proliferation.
– These cells have telomerase reactivated, allowing them to
maintain telomere length.
Telomerase and cancer cells
• Active telomerase found in 90% of human tumors.
• Telomerase does NOT cause cancer; it only allows cancer cells to
continue proliferation.
– These cells have telomerase reactivated, allowing them to
maintain telomere length.
• Cancer cells may activate telomerase through the G1-S checkpoint
• In 30% of human tumors, gene that codes for hTERT is amplified
(meaning more likely for telomerase to be active)
Cancer treatments involving telomeres
Cis-[Pt(Cl)2(pyridine)(5-SO3H-isoquinoline)] complex
• Known as Ptquin8 for short,
this selectively inhibits
telomerase activity
– Telomerase’s RNA template is
rich in guanine.
– Platinum based drugs such as
cisplatin, carboplatin, and
Ptquin8 have a high affinity
for these guanines in the N7
position.
– Does not completely inhibit
telomerase, but enough to
destabilize telomeric
homeostasis
Cancer treatments involving telomeres
Cis-[Pt(Cl)2(pyridine)(5-SO3H-isoquinoline)] complex
• Ptquin8 also will not interfere
with other genomic DNA
– However, Ptquin8 works
because of genetic alterations
• Active in low concentrations
(10-9 to 10-7 M)
• No aspecific cytotoxicity
– Not as harmful to other
healthy cells like
chemotherapy is
• Overall, a good cancer
treatment option
Telomeres and aging
• Cells generally divide 60-100x during lifespan
• Once telomeres shorten enough, cell enters senescence
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(aging)
Internal “clock” for cellular aging?
Telomerase would essentially reset the “clock”
Telomerase as anti-aging treatment
• Abnormally reactive in cancer cells
• Maintaining telomere length with telomerase in normal
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cells could lead to cancer
Needs cells to undergo division, some don’t (muscle and
nerve)
Overall aging of body (mechanical stress, etc.) cannot be
overcome simply by activating telomerase
– How much of a role does telomerase actually play?
Telomerase as a diagnostic tool
• Could be used as a marker for cancer diagnostics,
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prognosis, patient monitoring, and screening
Telomerase activity indicative of cancer cells
The future research
• Cells from diseased tissue can be telomerase-
immortalized
– Function comparably well to non-immortalized
counterparts
– Explore mechanism of disease
– Develop interventions for treatment and prevention
The future research
• Wound healing
• Tissue regeneration (ex: burn victims)
– Problem: How do you stop treated cells from
becoming cancerous?
The future research
• Age related diseases
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– Atherosclerosis, macular degeneration (eye)
Take patient’s cells, manipulate and rejuvenate them,
then reinsert them into their body
– Expansion of specific immune cells or nerve cell
precursors
 Possible treatements
 Immune deficiencies or neurodegenerative diseases
• Continued cancer research
– Peptide Epithalon and how it induces telomerase activity
Works cited
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Altshuler, M.L., S.E. Severin, and A.I. Glukhov. “The Tumor Cell and Telomerase.” Biochemistry (Moscow). Vol
68, No. 12, 2003, 1275-1283.
Clark, William R. A Means to an End: The Biological Basis of Aging and Death. Oxford University Press, New
York. 1999.
Colangelo, D., A. L. Ghiglia, I. Viano, G. Cavigiolio, and D. Osella. “Cis-[Pt(Cl)2(pyridine)(5-SO3H-isoquinoline)]
complex, a selective inhibitor of telomerase enzyme.” BioMetals 16: 553-560, 2003.
Li, H. and J-P Liu. “Signaling on telomerase: a master switch in cell aging and immortalization.” Biogerontology
3: 107-116, 2002.
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http://www.swmed.edu/home_pages/cellbio/shay-wright/research/sw_research.html