outline the role of telomeres in preventing the loss of genes from the ends of chromosomes during DNA replication

Replication and Division of Nuclei and Cells

Learning objective

Outline the role of telomeres in preventing the loss of genes from the ends of chromosomes during DNA replication.

1. Chromosome structure (syllabus requirement)

• DNA double helix wrapped around histone octamers → nucleosome → chromatin fibre.
• Sister chromatids – two identical copies of a replicated chromosome held together by the centromere.
• Centromere – region where kinetochores form and spindle fibres attach.
• Telomeres – specialised caps of repetitive, non‑coding DNA at each chromosome end.

2. The mitotic cell‑cycle (overview)

1. Interphase

   • G1 – cell growth, synthesis of proteins.
   • S – DNA replication (telomeres shorten here).
   • G2 – preparation for mitosis, checkpoint checks DNA integrity.

2. Mitosis – division of the nucleus

   • Prophase – chromatin condenses, spindle forms.
   • Metaphase – chromosomes line up at the metaphase plate; sister chromatids are attached at their centromeres.
   • Anaphase – sister chromatids separate and move to opposite poles.
   • Telophase – nuclear envelopes re‑form around each set of chromosomes.

3. Cytokinesis – division of the cytoplasm, producing two daughter cells.

3. The end‑replication problem

• DNA polymerase can only add nucleotides to an existing 3′‑OH group.
• On the lagging strand the final RNA primer cannot be replaced because there is no upstream 3′‑OH.
• Consequently a short stretch of DNA is lost from each chromosome end at every S‑phase.

4. Structure of telomeres

• DNA component: short tandem repeats (human example – TTAGGG repeated 5–15 kb).
• Protein component: the shelter‑in complex (TRF1, TRF2, POT1, TIN2, TPP1, RAP1) binds the repeats and creates a stable “cap”.

5. How telomeres prevent loss of essential genes

6. Role of telomerase – the only mechanism that restores telomere length

• Telomerase is a ribonucleoprotein enzyme; its RNA component provides the template (CUAACCA in humans).
• It adds telomeric repeats to the 3′ end of the DNA strand:

  
  DNAnew = DNAold + (TTAGGG)n

• Typical activity adds ~50–200 repeats (≈300–1 200 bp) per cell division.
• High activity in germ cells, embryonic stem cells, and most cancer cells; low or absent in most somatic cells, allowing gradual shortening.

7. Link to the cell‑cycle checkpoints

• Telomere shortening is sensed during G2/M checkpoints.
• When telomeres reach a critical length, p53‑mediated pathways trigger either cellular senescence (permanent growth arrest) or apoptosis, preventing damaged cells from entering mitosis.

8. Consequences of telomere shortening

1. Activation of DNA‑damage checkpoints.
2. Cellular senescence – loss of proliferative capacity (ageing of tissues).
3. Apoptosis if damage cannot be repaired.
4. Chromosome end‑to‑end fusions → aneuploidy and genomic instability.

9. Implications for stem cells and tumour formation

• Stem cells must maintain telomere length to support repeated divisions required for tissue repair; they retain telomerase activity.
• In many cancers, re‑activation of telomerase (or alternative lengthening of telomeres) allows cells to bypass senescence, contributing to uncontrolled cell division.

10. Behaviour of telomeres during mitosis

• During metaphase the telomeres remain attached to the kinetochores via the sister‑chromatid arms; they are not directly involved in spindle attachment but must be intact to avoid chromosome breakage.
• Proper telomere capping ensures that chromosomes segregate as whole units during anaphase.

11. Classroom activity – interpreting mitotic diagrams

Provide students with a labelled photomicrograph of each mitotic stage. Ask them to identify and label:

1. Centromere and kinetochores.
2. Sister chromatids.
3. Position of telomeres (highlighted as the terminal ends of each chromatid).
4. Any visible changes in chromosome condensation.

12. Summary

Telomeres act as protective, non‑coding caps that absorb the inevitable loss of DNA at chromosome ends during each S‑phase. By providing a buffer, they safeguard essential genes and prevent chromosome‑end fusions, thereby maintaining genome stability through many cell divisions. Telomerase replenishes this buffer in germ cells, stem cells, and most cancer cells, linking telomere dynamics to ageing, tissue repair, and tumour development.