Makindo Medical Notes

Related Subjects: |DNA and RNA short notes |DNA replication |DNA structure in Nucleus |Mitosis and Meiosis |Telomeres

🧬 Telomeres are repetitive DNA sequences at the ends of chromosomes that act as protective caps, preventing degradation and end-to-end fusion. They are central to genomic stability, cellular aging, and cancer biology.

🔬 Structure of Telomeres

• Nucleotide Sequence: Tandem repeats of TTAGGG (in vertebrates), extending thousands of base pairs.
• Shelterin Complex: A group of binding proteins (TRF1, TRF2, POT1, TIN2, TPP1, RAP1) that protect telomeres and regulate length.
• T-loop: Telomeres fold back on themselves, forming a protective loop that shields chromosome ends from DNA repair enzymes.

⚙️ Functions of Telomeres

• Chromosome End Protection 🛡️: Prevent recognition as DNA breaks → avoids degradation or fusion.
• Buffer Against Replication Loss ⏳: The "end-replication problem" causes gradual shortening with each cell cycle; telomeres act as a sacrificial buffer.
• Cellular Aging 👵: Critically short telomeres trigger replicative senescence (Hayflick limit) or apoptosis.
• Cancer Biology 🧪: Malignant cells often reactivate telomerase or use ALT (alternative lengthening of telomeres) to maintain immortality.

🧩 Telomerase & Maintenance

• Telomerase: A ribonucleoprotein enzyme with TERT (catalytic subunit) + TERC (RNA template). Active in germ cells, stem cells, and cancer cells; silent in most somatic tissues.
• ALT Pathway: Uses homologous recombination between telomeric regions as a telomerase-independent rescue mechanism in some tumours (e.g., osteosarcomas, glioblastomas).
• Stem Cells vs. Somatic Cells: Stem cells maintain telomerase activity → tissue renewal; somatic cells lack it → progressive aging.

🩺 Clinical Significance

• Aging & Degeneration: Short telomeres linked with frailty, atherosclerosis, diabetes, and Alzheimer’s disease.
• Cancer: Tumours sustain telomeres (via telomerase/ALT) → unlimited replication. Telomerase is being explored as a therapeutic target.
• Genetic Disorders:
  • Dyskeratosis congenita: Defective telomerase → premature aging, bone marrow failure, pulmonary fibrosis.
  • Aplastic anemia: Sometimes linked with short telomeres due to faulty stem cell renewal.

💊 Research & Therapies

• Telomerase Inhibitors: Experimental cancer therapies (e.g., imetelstat) aim to limit tumour immortality.
• Telomere Extension: Investigational approaches using telomerase activators to slow aging in experimental models.
• Biomarkers: Telomere length is being studied as a predictor of biological age, disease progression, and treatment response.

📌 Clinical Pearls

• Cells with very short telomeres → p53 pathway activation → senescence/apoptosis (tumour suppression mechanism).
• Cancers with defective p53 + telomere shortening → chromosomal instability → tumour progression.
• “Immortalized” cell lines (like HeLa cells) maintain growth through upregulated telomerase.

📝 Summary

Telomeres are the “chromosome caps” that dictate how many times a cell can divide. Their shortening drives aging and age-related disease, while their maintenance underlies cancer cell immortality. Understanding telomere biology opens doors to anti-cancer and anti-aging therapies.