Learning Objective: By the end of this section, the learner should be able to describe major DNA repair mechanisms, identify key enzymes involved, correlate repair defects with disease, and apply these concepts to clinical problem-solving.
DNA Damage and the Need for Repair
DNA is constantly exposed to internal and external insults—UV radiation, chemicals, heat, oxidative stress, and replication errors. Damage must be corrected before DNA replication proceeds, or mutations become permanent and heritable. Most DNA repair occurs during the G₁ phase, and mismatch repair occurs during G₂.
Major Types of DNA Damage
- Thymine (pyrimidine) dimers – UV radiation
- Mismatched bases – errors during DNA replication
- Cytosine deamination → uracil – spontaneous, heat-related
Overview of DNA Repair Pathways
1. Nucleotide Excision Repair (NER)
Corrects: Thymine dimers & bulky lesions
When: G₁ phase
- Excision endonuclease (excinuclease) detects distortion.
- Cuts phosphodiester bonds on both sides of the lesion.
- Removes damaged oligonucleotide.
- DNA polymerase synthesizes replacement DNA.
- DNA ligase seals the nick.
Disease Association – Xeroderma Pigmentosum
- Autosomal recessive
- Defective nucleotide excision repair (defective excinuclease)
- Extreme UV sensitivity, freckling, and skin cancers early in life
2. Base Excision Repair (BER)
Corrects: Cytosine deamination → uracil
- Uracil glycosylase removes uracil from DNA.
- AP endonuclease removes the damaged sugar–phosphate backbone.
- DNA polymerase fills the gap.
- DNA ligase seals the strand.
3. Mismatch Repair (MMR)
Corrects: Replication errors (misincorporated bases that escape polymerase proofreading)
When: Primarily G₂
Key enzymes
- MSH2, MLH1 detect and repair mismatches.
Disease Association – HNPCC (Lynch Syndrome)
- Mutation in hMSH2 or hMLH1
- Microsatellite instability hallmark
- Increased risk of colorectal, endometrial, and ovarian cancers
Genes Maintaining DNA Integrity
| Function | Genes |
|---|---|
| DNA synthesis proofreading | DNA polymerases (3’→5′ exonuclease) |
| Mismatch repair | MSH2, MLH1 |
| NER | XP genes |
| Cell cycle checkpoint | p53, Rb |
| DNA damage sensing | ATM |
Key Clinical Notes
- p53 mutation → Li-Fraumeni syndrome
- ATM mutation → Ataxia-telangiectasia (x-ray sensitivity, lymphoma risk)
- BRCA1/2 → impaired repair of double-strand breaks
Clinical Correlations
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