7.3 DNA Mutations and Repair Mechanisms

DNA mutations are changes in genetic material that can have far-reaching effects. From point mutations to frameshifts, these alterations can impact protein function and organism health. Understanding mutations is crucial for grasping how genetic information can be altered.

Luckily, our cells have built-in repair mechanisms to fix DNA damage. These processes, like mismatch repair and nucleotide excision repair, work tirelessly to maintain genetic integrity. However, when repair fails, mutations can lead to various health issues.

Types of Mutations

Point Mutations

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• Occur when a single nucleotide base is changed, inserted, or deleted in the DNA sequence
• Can be caused by exposure to mutagens (chemicals, radiation) or errors during DNA replication
• May have no effect on the protein produced (silent mutation), change the amino acid sequence (missense mutation), or create a premature stop codon (nonsense mutation)
• Examples include sickle cell anemia (GAG to GTG) and cystic fibrosis (deletion of phenylalanine at position 508)

Frameshift Mutations

• Involve the insertion or deletion of a number of nucleotides that is not divisible by three
• Shift the reading frame of the genetic code, altering the amino acid sequence of the protein produced
• Often result in a completely different protein or a truncated, non-functional protein
• Can be caused by slipped-strand mispairing during DNA replication or exposure to mutagens
• Examples include Tay-Sachs disease (insertion of four bases, GATC) and Duchenne muscular dystrophy (deletion of one or more exons)

Insertion, Deletion, and Substitution Mutations

• Insertion mutations occur when one or more nucleotides are added to the DNA sequence
• Deletion mutations occur when one or more nucleotides are removed from the DNA sequence
• Substitution mutations occur when one nucleotide is replaced by another (transition: purine to purine or pyrimidine to pyrimidine; transversion: purine to pyrimidine or vice versa)
• Can cause frameshift mutations if the number of inserted or deleted nucleotides is not divisible by three
• Examples include Huntington's disease (CAG trinucleotide repeat expansion) and color blindness (substitution in the red or green opsin gene)

DNA Repair Mechanisms

Mismatch Repair

• Corrects errors made during DNA replication, such as base-base mismatches or small insertion/deletion loops
• Involves recognition of the mismatch, excision of the incorrect nucleotide(s), and resynthesis using the correct nucleotide(s)
• Defects in mismatch repair genes (MSH2, MLH1) are associated with increased risk of hereditary nonpolyposis colorectal cancer (Lynch syndrome)

Nucleotide Excision Repair

• Repairs bulky DNA lesions caused by UV light (pyrimidine dimers), chemicals (benzo[a]pyrene), or chemotherapeutic agents (cisplatin)
• Recognizes distortions in the DNA helix, excises a segment of the damaged strand, and synthesizes a new strand using the undamaged strand as a template
• Defects in nucleotide excision repair genes (XPA, XPC, XPD) cause xeroderma pigmentosum, characterized by extreme sensitivity to UV light and increased risk of skin cancer

Base Excision Repair

• Corrects small, non-helix-distorting lesions such as oxidized, deaminated, or alkylated bases
• Involves recognition and removal of the damaged base by a DNA glycosylase, followed by excision of the remaining sugar-phosphate backbone and resynthesis
• Examples include repair of 8-oxoguanine (oxidative damage) by OGG1 and uracil (deamination of cytosine) by UNG

DNA Proofreading

• Occurs during DNA replication to ensure the fidelity of the newly synthesized strand
• DNA polymerases (Pol δ and Pol ε) have intrinsic 3'→5' exonuclease activity that allows them to remove misincorporated nucleotides
• Enhances the accuracy of DNA replication by 100-1000 fold, reducing the error rate to approximately 1 in 10^7 to 10^8 base pairs per replication

Mutation Causes

Mutagens

• Agents that increase the frequency of mutations in DNA
• Can be physical (UV light, ionizing radiation), chemical (alkylating agents, intercalating agents), or biological (viruses, transposons)
• Mutagens often cause specific types of mutations (UV light: pyrimidine dimers; alkylating agents: O6-methylguanine)
• Examples include cigarette smoke (polycyclic aromatic hydrocarbons), aflatoxin B1 (produced by Aspergillus flavus), and X-rays