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DNA Synthesis and Repair: Telomeres, Telomerase, and DNA Repair Mechanisms

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Chapter 15: DNA and the Gene – Synthesis & Repair

Introduction

This chapter explores the molecular mechanisms of DNA replication and repair, focusing on the challenges of replicating linear chromosomes, the role of telomeres and telomerase, and the cellular systems that maintain genetic fidelity. Understanding these processes is essential for grasping how cells preserve genetic information and how errors can lead to disease, including cancer.

DNA Replication: Key Enzymes and Processes

Opening the Helix

  • Helicase: Catalyzes the breaking of hydrogen bonds between base pairs to open the double helix.

  • Single-strand DNA-binding proteins (SSBPs): Stabilize single-stranded DNA during replication.

  • Topoisomerase: Breaks and rejoins the DNA double helix to relieve twisting forces caused by the opening of the helix.

Name

Structure

Function

Helicase

Breaks hydrogen bonds to open the helix

SSBPs

Stabilizes single-stranded DNA

Topoisomerase

Relieves twisting forces

Leading and Lagging Strand Synthesis

  • Primase: Synthesizes RNA primers required for DNA polymerase to begin synthesis.

  • DNA Polymerase III: Extends the leading strand and Okazaki fragments on the lagging strand.

  • Sliding Clamp: Holds DNA polymerase in place during strand extension.

  • DNA Polymerase I: Removes RNA primers and replaces them with DNA.

  • DNA Ligase: Joins Okazaki fragments to create a continuous DNA strand.

Process

Enzyme

Function

Leading Strand

Primase, DNA Polymerase III, Sliding Clamp

Continuous synthesis

Lagging Strand

Primase, DNA Polymerase III, Sliding Clamp, DNA Polymerase I, DNA Ligase

Discontinuous synthesis (Okazaki fragments)

Replicating the Ends of Linear Chromosomes

The End Replication Problem

Linear chromosomes present a unique challenge during DNA replication, particularly at their ends (telomeres).

  • The leading strand is synthesized to the end, but the lagging strand leaves a single-stranded overhang.

  • DNA polymerase cannot add nucleotides without a primer, resulting in incomplete replication of the lagging strand.

  • Each round of replication shortens the chromosome by 50–100 nucleotides.

  • Telomeres consist of short, repeating stretches of bases and do not contain genes.

Chromosome Shortening During Replication

  • Single-stranded DNA left at the end of the lagging strand is degraded.

  • Over time, this would lead to the loss of genetic material if not addressed.

Telomeres and Telomerase

Discovery and Function

  • Elizabeth Blackburn discovered that the ends of eukaryotic chromosomes (telomeres) have no genes and consist of repeated DNA sequences.

  • Telomerase is the enzyme responsible for replicating telomeres, using an RNA template that it carries.

Mechanism of Telomerase

  • The 3' end of the lagging strand forms a single-stranded overhang.

  • Telomerase binds to the overhang and uses its RNA template to extend the DNA.

  • Telomerase adds short DNA sequences to the end, allowing normal DNA synthesis to occur.

Telomerase Prevents Chromosome Shortening

  • By extending telomeres, telomerase ensures that only dispensable repeat DNA is lost, not important genes.

  • Blackburn and Carol Greider discovered telomerase in Tetrahymena cells and won the Nobel Prize in 2009.

Telomerase Regulation

  • Somatic cells normally lack telomerase, leading to progressive telomere shortening and cellular aging.

  • Two hypotheses for telomerase regulation:

    • Once chromosomes are shortened to a threshold length, cell division stops and cells enter G0.

    • If telomerase is mistakenly activated, cells may divide uncontrollably, possibly leading to cancer.

  • Adding telomerase to human cells in vitro allows continued cell division.

Telomerase and Cancer

Canadian Research 15.1: Telomerase and Cancer

  • Healthy somatic cells can divide about 50 times before telomeres become too short.

  • Cancer cells bypass this limit and divide continuously.

  • In 85% of cancer cells, telomeres are maintained by telomerase; in 15%, an alternative lengthening of telomeres (ALT) system is used.

Cell Type

Telomerase Activity

Division Potential

Normal Somatic Cell

Absent

Limited (~50 divisions)

Cancer Cell

Present (or ALT)

Unlimited

Therapeutic Approaches

  • Telomerase inhibitors have been tested in mouse and human cancer cells.

  • Cancer cells can adapt by increasing telomerase production or switching to ALT.

  • Anticancer drugs targeting telomerase or telomere maintenance are under development.

Canadian Research 15.2: Telomeres and Cancer

  • Lea Harrington's lab found that cancer cells with artificially long telomeres (12,000–24,000 bp) were more sensitive to radiation.

  • Questions remain about whether longer telomeres increase DNA damage susceptibility or recruit repair enzymes away from other sites.

Correcting Mistakes in DNA Synthesis

DNA Replication Accuracy

  • DNA replication is highly accurate, with an error rate of about one mistake per billion bases.

  • DNA polymerase matches bases with high specificity, but occasionally inserts incorrect bases (about one per 100,000).

  • Repair enzymes correct defective bases.

DNA Polymerase Proofreading

  • DNA polymerase can proofread its work, removing mismatched bases via its epsilon subunit.

  • This proofreading reduces the error rate to about one mistake in 10 million base pairs.

Mismatch Repair

  • Mismatch repair enzymes correct errors left after DNA synthesis.

  • They recognize mismatched pairs, remove the incorrect section, and fill in the correct bases.

Repairing Damaged DNA

  • DNA can be damaged by UV light, X-rays, and chemicals, causing lesions such as thymine dimers.

  • Organisms have DNA damage-repair systems to address these issues.

Nucleotide Excision Repair

  • A protein complex recognizes DNA damage (e.g., kinks from thymine dimers).

  • The damaged single-stranded DNA is removed.

  • The intact strand serves as a template for new DNA synthesis.

  • DNA ligase links the repaired strand to the original undamaged DNA.

DNA Repair and the Cell Cycle

  • Interphase DNA repair includes proofreading, mismatch repair, nucleotide excision repair, and double-strand break (DSB) repair.

  • DSB repair is inactivated during mitosis to prevent chromosome fusion at telomeres, which is catastrophic for cells.

  • DNA repair is halted during mitosis to avoid damaging chromosomes.

Check Your Understanding

  • Telomere shortening limits cell division; telomerase can extend cell lifespan.

  • Adding telomerase to cells eliminates telomere shortening and retards aging.

Learning Objectives

  • Explain why one strand of DNA at the end of a chromosome cannot be replicated to its end and how telomerase solves this problem.

  • Describe how proofreading, mismatch repair, and nucleotide excision repair work and why they are important.

Additional info: The notes have been expanded with definitions, mechanisms, and context for telomere biology, DNA replication, and repair systems, as well as their relevance to cancer biology.

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