Which strand template fails to be completely copied by DNA (Deoxyribonucleic acid) polymerase when a replication fork approaches the end of a human chromosome?

The Lagging Strand Template Fails to Be Completely Copied at Chromosome Ends

When a replication fork approaches the end of a human chromosome, the lagging strand template fails to be completely copied by DNA polymerase. 1

Mechanism of End Replication Problem

The end replication problem occurs due to the fundamental mechanics of DNA replication:

1. DNA Polymerase Directionality: DNA polymerase can only synthesize DNA in the 5' to 3' direction and requires an RNA primer to initiate synthesis 1

2. Leading vs. Lagging Strand Synthesis:

   • Leading strand: Synthesized continuously in the 5' to 3' direction
   • Lagging strand: Synthesized discontinuously as Okazaki fragments, each requiring an RNA primer 1

3. Terminal Problem: When the replication fork reaches the chromosome end:

   • The leading strand can be synthesized completely to the very end
   • The lagging strand cannot be completed because there is no place to put the final RNA primer that would be needed to synthesize the terminal DNA segment 1

Molecular Consequences

This incomplete replication of the lagging strand template results in:

• Progressive shortening of telomeres with each cell division 1
• Loss of 50-200 base pairs per cell division at chromosome ends
• Eventually, critically short telomeres trigger DNA damage responses 1
• Cellular senescence or apoptosis when telomeres become critically short 1

Biological Significance

The end replication problem has significant implications for:

• Cellular Aging: Telomere shortening is a molecular clock that limits cell divisions 1
• Disease Risk: Short telomeres are associated with increased cardiovascular risk and reduced immune function 1
• Cancer Development: Cells must overcome this limitation to become immortalized, often by activating telomerase 1

Common Misconceptions

• Both Strands Issue: While both strands face challenges at chromosome ends, only the lagging strand template has the fundamental problem of incomplete replication
• Leading Strand Completion: The leading strand can theoretically be synthesized to the very end of the chromosome, though other factors may affect its completion

The end replication problem is a fundamental limitation of DNA replication that contributes to cellular aging and has driven the evolution of telomeres as protective chromosome caps that buffer against the loss of essential genetic information.