Telomere_DNA_replication

DNA Replication: Overview

DNA Polymerase

• Definition: DNA polymerase is a critical enzyme involved in the replication of DNA, facilitating the elongation of new DNA strands.

• Function: It ensures the accurate addition of nucleotides complementary to the template strand, proofreading its work to prevent mutations during DNA synthesis.

Replication Viewed from Two Angles

• End-on: This perspective shows the replication fork where the DNA strands begin separating.

• Side-on: This view illustrates how the polymerase moves along the template strand, synthesizing the new strand.

Chromosome Structure

Prokaryotic vs. Eukaryotic Chromosomes

• Chromosome: A chromosome is a long, continuous molecule of DNA that carries genetic information, typically varying from thousands to millions of base pairs in length.

Prokaryotic Chromosome:

• Shape: Circular structure, which is simpler compared to eukaryotic chromosomes.

• Location: Found freely in the cytoplasm (nucleoid region) as prokaryotes lack a defined nucleus.

Eukaryotic Chromosome:

• Shape: Linear structure, allowing for more complex organization of genetic material.

• Structure: Condensed and organized around histone proteins, forming nucleosomes, which facilitate efficient packaging of DNA into the nucleus.

• Location: Found within the membrane-bound nucleus of the cell, further organized into chromatin.

Telomeres

Definition and Structure

• Telomeres: Specialized structures comprising repetitive DNA sequences and associated proteins located at the ends of eukaryotic chromosomes.

• Composition: Comprised of repeated sequences of bases, the human telomere sequence is 5’ TTAGGG 3’.

• Length: Telomeres can be repeated approximately 3,000 times, resulting in lengths that can reach up to 15,000 base pairs, playing a significant role in chromosome stability.

Functions of Telomeres

• Organization: Play a critical role in organizing chromosome positioning within the nucleus, contributing to overall cell function and health.

• Protection: Act as protective caps to shield chromosome ends from the processes that could lead to degradation or fusion with other chromosomes, which could destabilize genetic information.

• Replication Support: Ensure proper replication of genetic material during cell division, facilitating the preservation of genetic integrity.

DNA Replication and Telomeres

• Loss during Replication: Every DNA replication cycle results in the loss of approximately 25-200 bases from the chromosome ends, mainly affecting telomeric DNA.

• Critical Length: Once telomeres shorten beyond a critical length, they can no longer protect chromosomes, leading to the cessation of cell division and contributing to the cellular aging process.

Telomerase

Function and Role

• Telomerase: An enzyme with the ability to elongate telomeres, thus allowing cells to undergo continuous division without aging.

• Mechanism: It adds guanine-rich repetitive sequences (5’ TTAGGG 3’) to telomeres, counteracting progressive shortening during replication.

Distribution and Activity

• Concentration: Telomerase concentration is low in somatic (body) cells, while it is high in gametes (sperm and egg cells), stem cells, and certain tumor cells, facilitating their ability to divide indefinitely and avoid senescence.

Mechanism of Chromosome Shortening During Replication

Steps in DNA Replication

1. Unwinding: Helicase unwinds the DNA helix at the replication fork, separating the two strands of DNA.

2. Leading Strand: The leading strand is synthesized continuously by DNA polymerase moving toward the replication fork.

3. Lagging Strand: The lagging strand synthesis is more complex:

   • RNA Primer: Primase synthesizes an RNA primer to initiate synthesis.

   • Okazaki Fragments: DNA polymerase synthesizes the lagging strand in short segments called Okazaki fragments.

   • Final Steps: After the removal of the RNA primer, there is no free 3' end available for DNA polymerase to continue synthesis, leading to potential shortening of the chromosome ends.

Maintenance of Telomere Length

• Reverse Transcriptase Activity: Telomerase utilizes reverse transcriptase activity to synthesize complementary DNA, using its RNA template at the 3' end of the chromosome, effectively counteracting the natural loss of telomere length during replication.

• Addition of Sequences: Repetitive sequences of 5’ TTAGGG 3’ are added, ensuring that functional telomeres are maintained over successive rounds of cell division.

Challenges in Lagging Strand Replication

• Free 3' End Requirement: The lagging strand faces challenges at its 3' end due to the necessity of a free 3' end for DNA polymerase activity, resulting in incomplete replication and contributing to the progressive shortening of DNA with each replication cycle.