DNA is constantly damaged by environmental agents (UV light, chemicals, radiation) and internal errors during replication.
To preserve genomic integrity, cells have evolved multiple repair pathways that detect and fix damaged DNA.
Failures in these repair systems lead to mutations, cancer predisposition, and genetic diseases.
Types of DNA Repair Mechanisms
| Type | Mechanism | Key Phase in Cell Cycle | Clinical Significance / Defects |
|---|---|---|---|
| Nucleotide Excision Repair (NER) | Removes bulky, helix-distorting lesions (e.g., thymine dimers). Specific endonucleases excise damaged bases, and DNA polymerase fills in the gap. | G₁ phase | Defective in Xeroderma pigmentosum → UV sensitivity, skin cancer. |
| Base Excision Repair (BER) | Removes single altered bases due to deamination or oxidation. Involves glycosylase, AP endonuclease, DNA polymerase, and ligase. | Throughout the cell cycle | Repairs spontaneous/toxic deamination. Mnemonic: “GEL Please” → Glycosylase, Endonuclease, Lyase, Polymerase, Ligase. |
| Mismatch Repair (MMR) | Corrects replication errors in newly synthesized DNA strands. | S phase | Defective in Lynch syndrome (HNPCC). |
| Nonhomologous End Joining (NHEJ) | Joins broken double-stranded DNA ends without requiring homology. Often causes loss or translocation of DNA fragments. | G₁ phase (mainly) | Defective repair increases the risk of translocations, seen in radiation injury. |
| Homologous Recombination (HR) | Uses a complementary intact DNA strand as a template to accurately repair double-strand breaks. | S and G₂ phases | Defective in BRCA1/BRCA2 mutations and Fanconi anemia. |
Key Points to Remember
- NER fixes thymine dimers (UV damage).
- BER fixes small base changes (e.g., cytosine → uracil).
- MMR corrects replication mismatches in new DNA.
- NHEJ = quick but error-prone repair of double-strand breaks.
- HR = accurate double-strand repair using homologous DNA template.
- Defective DNA repair → cancer syndromes, premature aging, or neurodegeneration.
Learning Objective
By the end of this module, the student should be able to:
Identify and differentiate between the major DNA repair pathways, describe their key enzymes, and associate their defects with clinical conditions tested on the USMLE Step 1.
