Telomeres and Aging - Page-by-Page Notes
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- Learning objectives:
- Explain the genetic factor in cell aging via telomere shortening with every cell division.
- Explain how telomerase can reverse telomere shortening in cancer, germ cells, and stem cells.
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- Core concepts:
- Telomere shortening contributes to aging by reducing replicative capacity; telomerase extends telomeres in cells where it is active (germ, stem, many cancer cells).
- Telomerase is a ribonucleoprotein that uses an RNA template to add telomere repeats.
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- End Replication Problem:
- Linear chromosomes are not fully replicated by DNA polymerase; 5' ends are not completely copied, leading to progressive shortening.
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- Replication dynamics:
- Leading strand synthesized continuously; lagging strand synthesized discontinuously as Okazaki fragments; RNA primers required.
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- RNA primer removal and gaps:
- Removal of RNA primers leaves gaps between fragments; ends are not fully replicated.
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- Primer removal consequences:
- Gaps persist between Okazaki fragments until ligation.
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- Ligase:
- Ligase seals nicks to form a continuous strand.
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- End gaps:
- Each round of replication leaves 50-200\text{ bp} unreplicated at the 5' end.
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- Circular DNA:
- Most bacterial DNA is circular; circular genomes have no ends and thus no end replication problem.
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- Telomeres as a temporary solution:
- Telomeres consist of non-coding repeats of \text{TTAGGG} in humans.
- They protect coding regions and help prevent loss of genetic information, replicative senescence, and apoptosis; chromosome ends are not treated as breaks.
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- Implications of telomere shortening:
- Telomere length correlates with proliferative capacity and finite replicative life span (mortal).
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- Possible outcomes of telomere shortening:
- Senescence, apoptosis, or limited proliferation.
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- Senescence and Hayflick limit:
- Normal cells stop dividing when telomeres reach a critical length; Hayflick limit defines this replicative cap; prevents proliferation of damaged cells.
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- Telomere shortening as a driver of aging:
- Shortened telomeres contribute to aging through progressive tissue decline and cell loss.
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- Telomerase activity distribution:
- Active in germ cells, gametes, epidermal stem cells, hair follicle stem cells, some immortalized cells, and the majority of cancer cells.
- Inactive in most somatic/differentiated/post-mitotic cells.
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- Telomerase composition:
- Telomerase is a ribonucleoprotein enzyme complex.
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- Telomerase mechanism basics:
- Telomere repeat sequence: \text{TTAGGG} repeats; telomere overhang with a 5' to 3' orientation; telomerase extends the 3' end.
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- Telomere extension concept:
- Telomerase adds repeats to the 3' end, creating a longer overhang; gaps remain if extension is incomplete.
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- Telomerase RNA template:
- Telomerase uses its RNA component as a template to extend the telomere.
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- Continued extension and synthesis:
- After extension, DNA polymerase synthesizes the complementary strand with help of RNA primers; ligase seals.
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- Resulting telomere length:
- Extended telomere length achieved through coordinated telomerase extension and conventional replication.
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- Telomerase activity in cells:
- Activity is observed in cells that are immortal or far from replicative senescence.
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- Stem vs. somatic cells:
- Embryonic stem cells: longer telomeres + active telomerase.
- Somatic cells: shorter telomeres + inactive telomerase.
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- Why do we age?
- Telomere dynamics contribute to aging; telomere shortening leads to senescence and functional decline.
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- Key relationships:
- Telomeres regulate replicative capacity; telomerase maintains telomere length; cancer links telomere maintenance to uncontrolled division and apoptosis pathways.
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- Resources:
- The Science of Aging: https://www.youtube.com/watch?v=BkcXbx5rSzw
- End Replication problem: https://www.youtube.com/watch?v=5emqrkIvlTY
- Telomerase: https://www.youtube.com/watch?v=i6nE6gUp2cw