DNA Repair and Mutations Overview

Learning Objectives and Exam Revision Advice

• Students should be able to discuss and give examples of multiple DNA repair mechanisms.
• Students should be able to discuss different types of mutations and describe the methods used to repair DNA replication errors.

Introduction: Mutations

• A heritable change in the genetic material.
• Mutations provide allelic variations, which are important for evolutionary change.
• Mutations can be harmful and often cause diseases.
• Organisms have developed ways to repair damaged DNA.

Types of Mutations

• There are three main types of mutations:
  • Chromosome mutations: Changes in chromosome structure.
  • Genome mutations: Changes in chromosome number.
  • Gene mutations: Small changes in DNA structure that affect a single gene.

Gene Mutations

• Mutations can be point mutations or larger mutations.
  • Point mutations: A change in one base.
    • Insertion: Addition of one or more nucleotides.
    • Deletion: Removal of one or more nucleotides.
    • Inversion: Flipping a fragment of DNA.

Point Mutations: Silent

• A change in a base pair (bp) can cause a change in mRNA, but does not change the amino acid sequence of the protein.

Point Mutations: Neutral

• A change in bp causes change in mRNA and amino acid substitution, but no detectable change in the properties of the amino acid.

Point Mutations: Missense

• A change in bp causes change in mRNA and a different amino acid.

Point Mutations: Nonsense

• A change in bp causes a change in mRNA to a STOP codon (UAG, UAA, or UGA). No amino acid is produced.

Larger Mutations: Insertion/Deletion

• Insertion or deletion of base pairs (bp).
• The change in bp will alter the reading frame downstream.
• This can create new stop codons and change the length of the polypeptide.

Mutations Can Occur From DNA Replication Errors

• Replication machinery makes approximately one mistake per 10 million nucleotides copied.
• A mismatch error happens when the wrong base is incorporated; this needs to be corrected to avoid mutations. Errors need a backup system to recognise and correct mistakes, such as DNA mismatch repair (MMR).

DNA Mismatch Repair (MMR)

• MMR protein recognises mismatch errors.
• A section of the new strand with the error is cut out and replaced.
• DNA polymerase replaces the wrong DNA.
• DNA ligase seals the gap.

DNA Damage Can Occur Spontaneously

• Rare mistakes in DNA replication are corrected.
• DNA can be damaged in other ways, requiring different repair mechanisms, like chemical reactions.
• Random interactions between DNA and surrounding molecules can cause damage to the DNA sequence.
• Depurination and deamination are examples of these chemical reactions.
• If chemical modification of nucleotides is not repaired, it results in mutations.

DNA Damage Can Occur in Response to Mutagens

• Mutations can be caused by environmental mutagens—agents that cause DNA changes.
  • Radiation (UV and X-rays)
  • Chemicals (base analogues, base modifying agents, and intercalating agents).

Radiation as Mutagens

• Ionising radiation (X-rays) causes single-strand and double-strand DNA breaks.
• Non-ionising radiation (UV light) causes thymine dimers.

Chemicals as Mutagens

• Base analogues resemble DNA bases and are incorporated during replication, potentially causing mismatches (e.g., 5-Bromouracil).
• Base-modifying agents react with DNA bases, changing their structure.
• Intercalating agents, such as ethidium bromide, insert themselves between DNA base pairs, distorting the double helix and causing problems during replication.

Repair of DNA Damage

• Two general types of repair systems:
  • Direct reversal systems correct damaged areas by reversing the damage directly.
  • Excision repair systems cut out damaged areas, repair the gap with new DNA synthesis, and seal those gaps.
    • Base Excision Repair (BER)
    • Nucleotide Excision Repair (NER)
  • Non-Homologous End Joining (NHEJ)
  • Homologous Recombination (HR)

DNA Repair and Disease

• Mutations in genes encoding DNA repair proteins are associated with hereditary cancers.
  • Hereditary nonpolyposis colorectal cancer (mismatch repair)
  • Xeroderma pigmentosum (nucleotide excision repair)

Summary

• DNA mutations can occur spontaneously or due to environmental damage.
• DNA repair mechanisms exist to maintain DNA fidelity.
• Many different DNA repair mechanisms exist to correct replication errors and DNA damage.