Telomeres and Their Functions

Telomeres

• Telomeres are the ends of chromosomes in eukaryotic cells.
• They have three primary functions:
  • Prevent chromosomal degradation.
  • Prevent fusion of chromosome ends.
  • Facilitate faithful replication of linear DNA ends.
• Telomeres have a unique, short repetitive sequence.
  • Human telomeres contain the repeat sequence TTAGGG, highly conserved in vertebrates.
  • This repeat sequence is repeated hundreds to thousands of times.
  • Telomere length shortens with age in normal somatic cells.
  • Cancerous and germ cells maintain telomere length.
• The 3' end of a telomere is a single-stranded overhang.
  • Overhang length varies between organisms.
  • Human overhangs are typically 125-275 bases.
  • It is G-rich, allowing for non-Watson-Crick base-pairing. G-quartet formation and T-loop formation stabilize the telomere.
• Telomerase is essential for telomere replication.
  • It's composed of an RNA template (TERC) and a reverse transcriptase catalytic subunit (TERT).
  • Telomerase uses the G-rich strand as a template to synthesize new DNA at the 3' end.
  • DNA polymerase fills the lagging strand. Repeating these processes lengthens telomeres.
• Telomerase activity is often elevated in cancer cells.

Replicative Senescence

• In dividing human cells, telomeres gradually shorten.
  • This leads to cellular senescence, an irreversible loss of the ability to divide in culture.
  • Senescent cells undergo morphological changes, express specific marker genes (like SA-β-galactosidase), and display altered behaviors (SASP).
  • Shortened telomeres can activate cellular senescence despite growth factors and glucose being present.
• Signal from shortened telomeres activate Rb, p53, and p16Ink4A, inducing replicative senescence.
• Cancer cells can bypass senescence through the expression of the TERT subunit or through alternative mechanisms.
• In mouse cells, senescence bypass is linked to altered p16/p19 INK4A functioning indirectly through p19ARF stabilization of p53.
• Senescence can also be induced by cellular stress, activating p53 and Rb/p15 pathways, even independent of telomere erosion, by uncovering telomere ends alone.

Telomere Dysfunction and Cancer

• Prolonged culture of human cells leads to the Hayflick limit, activating checkpoints like Rb, p53, and p16InkA and triggering replicative senescence.
  • Bypassing these checkpoints leads to crisis, with chromosomal instability due to breakage-fusion-bridge cycles. This creates amplified, deleted regions generating large amounts of damage and new mutations.
• Telomere dysfunction can activate apoptosis.
  • If apoptosis is bypassed, cancer cells may reactivate telomerase (majority of cases) or use a mechanism called ALT to stabilize telomeres, which allows cells to grow.
• Ongoing epithelial turnover during aging, coupled with somatic mutations disabling oncogenic checkpoints, can lead to telomere shortening and genomic instability, contributing to carcinogenesis.
• This instability and mutations associated with telomere attrition can contribute to cancer progression.
• P53 mutation can attenuate growth arrest and apoptotic phenotypes, accelerating tumor development.

Angiogenesis

• Angiogenesis is the formation of new blood vessels from existing ones.
• Key cell types involved in angiogenesis are vascular endothelial cells, pericytes, and smooth muscle cells.
• Angiogenesis is crucial for tumor growth and delivery of anti-cancer therapeutics.
• Factors like VEGF, Ang1, Ang2, and PDGF influence these processes.
• VEGF is a major regulator of angiogenesis.
• Ang1 promotes vascular integrity by recruiting pericytes.
• Ang2 destabilizes the vascular structure.
• Pro-angiogenic factors (e.g., VEGF) and anti-angiogenic factors counteract each other. The balance between these factors determines the outcome.
• Statins and other molecules can inhibit angiogenesis.

This quiz covers the essential aspects of telomeres, including their structure, functions, and significance in cellular biology. You will learn about the repetitive sequences, telomere length dynamics, and the roles of telomerase in telomere replication. Test your knowledge on eukaryotic cell chromosome ends and their impact on aging and cancer.