Telomeres and Telomerase

1
Telomeres and Telomerase

• the internal clock is ticking

2
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.

3
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

4
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.

5
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

6
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

7
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
• When telomeres shorten too far, it may either
  cause altered gene expression or signal for
  apoptosis.

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Telomeres and diseases

• Shortened telomeres may be the culprit to such
  diseases as
• Diseases of premature aging
• Downs 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

9
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

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Telomerase
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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.

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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)

13
Cancer treatments involving telomeres
Cis-Pt(Cl)2(pyridine)(5-SO3H-isoquinoline)
complex

• Known as Ptquin8 for short, this selectively
  inhibits telomerase activity
• Telomerases 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

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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

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Telomeres and aging

• Cells generally divide 60-100x during lifespan
• Once telomeres shorten enough, cell enters
  senescence (aging)
• Internal clock for cellular aging?
• Telomerase would essentially reset the clock

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Telomerase as anti-aging treatment

• Abnormally reactive in cancer cells
• Maintaining telomere length with telomerase in
  normal cells could lead to cancer
• Needs cells to undergo division, some dont
  (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?

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Telomerase as a diagnostic tool

• Could be used as a marker for cancer diagnostics,
  prognosis, patient monitoring, and screening
• Telomerase activity indicative of cancer cells

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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

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The future research

• Wound healing
• Tissue regeneration (ex burn victims)
• Problem How do you stop treated cells from
  becoming cancerous?

20
The future research

• Age related diseases
• Atherosclerosis, macular degeneration (eye)
• Take patients 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

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Works cited

• 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.
• http//www.geron.com/
• http//www.swmed.edu/home_pages/cellbio/shay-wrigh
  t/research/sw_research.html