Telomeres & Telomerase
Immortality or Death
By Gretchen K. DeLue
What are Telomeres ?
• Specialized Proteins
• Simple Repetitive DNA nucleotide sequence, located on ends of
chromosomes
• (TTAGGG)
• (AATCCC)
• multiple repeats of this hexanucleotide sequence over a 5kb
span
• Double-stranded telomeric repeats with only the extreme
terminus consisting so single-stranded G-rich sequences (Gstrand/3’-single-stranded overhang
• Protective Caps that serve as Buffers on Chromosomal Ends (15,000
BP long)
Telomere Function
• Essential for Maintaining the Integrity of DNA near Ends of
Chromosomes
• Stabilizes Chromosome
• Protects from Deterioration and/or Merging with other
Chromosomes
- Preventative against Chromosomal Rearrangement/ Sticking together
• Act as marker to distinguish between gaps and ends of DNA
•Telomere Function is controlled by 2 Methods
1.) Erosion- Occurs each time cell divides
2.) Addition- Determined by action of Telomerase
Telomere Figures
•In a Human blood cell
•-8000 telomeres at birth
•-3000 telomeres in middle adulthood
•-15oo in elderly adult
- 30 to 200 base pairs lost from the ends of telomeres with each cell division
- Progressively shorten with each completion of mitosis
- Cell can divide around 50 to 70 times until telomeres become progressively shorter
The Problem with Replication
•Telomeres degrade further with each cell division
•DNA is replicated bilaterally
•DNA polymerases act unidirectionally
•DNA polymerase require primer to initiate replication
•20-500 base pairs unreplicated at 3’ end, each round of cell replication
•Cells with telomeres are 10-12kb in length
•Once telomeres are 4-6kb, cell dies
What is Telomerase ?
• Enzyme that repairs telomeres at the end of DNA by
synthesizing telomeres
• Restores telomeres to 3’end using own RNA as template
• Responsible for maintaining telomere length
• Located only in reproductive cells in humans; Telomerase is
not active in other cells
• Distinct sub-group of Proteins because so similar between
diverse species
Subunit Structure:
- composed of a catalytic
subunit, hTERT (human
telomerase reverse
transcriptase)
-hTER (human telomerase
ribonucleic acid)
-Various other proteins
-- Repairs telomeres located
at ends of DNA
- Elongates telomeric DNA
at its 3’ overhang
• Telomerase Structure:
- Multi-subunit specialized
ribonucleoprotein complex
- Composed of:
- TERC (Internal Telomerase RNA
Template)
&
- TERT (Telomerase Reverse
Transcriptase)
Regulatory Factors of Telomerase
• TERT: Catalytic component of the telomerase holoenzyme complex main
activity is the elongation of telomeres by acting as a reverse transcriptase, adds
simple sequence repeats to chromosome ends by copying a template sequence
within the complex
• The catalytic cycle involves primer binding, primer extension and release of
product once the template boundary has been reached
• Followed by further extension.
•Telomerase activity is regulated by a number of factors
-telomerase complex-associated proteins
-chaperones and polypeptide modifiers (modulates Wnt) signaling. Plays
important roles in aging and antiapoptosis
Telomerase Reverse Transcriptase
•TERT/hTERT
• Subunit of Enzyme Telomerase (RNA component of the enzyme)
• Catalytic component of the telomerase holoenzyme complex
• Main activity is the elongation of telomeres by acting as a reverse transcriptase
• Adds simple sequence repeats to chromosome ends by copying a template sequence within
the RNA component of the enzyme.
• Catalyzes the RNA-dependent extension of 3'-chromosomal termini with the 6-nucleotide
Telomeric repeat unit, 5'-TTAGGG-3'.
• More Active in sequences with 2 or 3 telomere repeats
• Genome studies implicate TERT as gene responsible for many types of cancer
Telomerase Paradox
-The Absence of telomerase is correlated to telomere shortening,
which is associated with aging and ultimately death of the somatic
cells
-However….
Highly active telomerase is present in over 90% of cancer cells in
humans.
- Theorized that the lack of Telomerase is a natural defense against
developing cancer cells
Telomerase Expression
• Telomerase
expression
plays a role in cellular
senescence, as it is normally
repressed in postnatal
somatic cells resulting in
progressive shortening of
telomeres.
• Deregulation of telomerase
expression in somatic cells
may be involved in
oncogenesis.
Senescence: Cellular Aging
• Process by which cells
become old and die
• Due to shortening of
telomeres causing
chromosome to reach critical
length
• What if Telomerase was in all
somatic cells?
Telomerase & Cancer
• The presence of telomerase is what allows cancer to proliferate
• 10-20 times the normal presence of telomerase is detected in malignant cancer
cells
•Cancer cells are considered to be immortal cells since high levels of telomerase
constantly repairs telomeres on end of cancer genome by adding new
nucleotides
•If telomerase activity could be turned off, the telomeres would inevitably
shorten within the cancerous cell
•This shortening would ultimately make replication impossible, cancer would
then be mortal rather then immortal just as human somatic cells are currently
mortal by the same action.
Cancer Detection/Treatment
• Measuring telomerase may be a new way to detect cancer.
• Inhibiting/Stopping Telomerase in cancer cells theoretically would cause cells
to age and die.
• Studies have blocked telomerase activity in human breast and prostate cancer
cells in laboratory setting, prompting the tumor cells to die.
Risks of Blocking Telomerase:
Impairs:
- Fertility
- Wound healing,
- Production of blood cells
- Immune system cells.
Telomere Shortening & Aging
•Shorter telomeres linked to shorter lives and higher
susceptibility to infectious disease
•Adults over age 60 with shorter telomere sequences were
3 times more likely to develop heart disease and 8 times
more likely to circum to infectious disease
•Unclear whether telomere shortening actually contributes
to/or is an attribute of the aging process.
Telomerase & Immortality
• Estimates
currently concede 30 years of life may be added by
lengthening telomere
•Adults over 60 with longer telomeres live an average of five
years longer
•If gene that produces telomerase can be turned on, the aging
process may be slowed, reversed or stopped entirely
•If all aspects that contribute to aging were eliminated, it is
estimated people may live 1000 years.
References
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References
AMA(American Medical Assoc.)Reference ListLuis E. D. Telomeres in cancer and ageing. Philosophical Transactions Of The Royal Society B: Biological
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