Introduction:
DNA repair is a vital cellular process that ensures genetic stability by correcting damage caused by replication errors, radiation, or chemical agents. Without proper repair, such damage could lead to mutations, cancer, or cell death.
The cell possesses an inbuilt system to identify and correct DNA damage through four major repair mechanisms:
- Base Excision Repair (BER)
- Nucleotide Excision Repair (NER)
- Mismatch Repair (MMR)
- Double-Strand Break Repair (DSBR)
1. Base Excision Repair (BER):
Base Excision Repair is responsible for removing small, non-helix-distorting base lesions such as those resulting from deamination, oxidation, or alkylation of bases.
Mechanism:
- Spontaneous deamination of cytosine, adenine, and guanine produces abnormal bases—uracil, hypoxanthine, and xanthine, respectively.
- These abnormal bases are recognized and removed by the enzyme Uracil DNA glycosylase.
- An endonuclease then cuts the DNA backbone near the defect and removes a few surrounding bases.
- The gap is filled by DNA polymerase and sealed by DNA ligase, restoring the normal DNA sequence.
Example:
This process corrects deamination-induced base changes, such as cytosine converting into uracil, preventing mutations from being propagated during replication.
2. Nucleotide Excision Repair (NER):
Nucleotide Excision Repair corrects bulky, helix-distorting DNA lesions caused by ultraviolet (UV) light, ionizing radiation, or chemical exposure. Such damage often leads to thymine dimers and cross-linkages.
Steps in NER:
- Recognition of the damaged DNA segment.
- Unwinding of the DNA double helix around the lesion.
- Cutting of the DNA strand on both sides of the damaged region by excision nuclease (exinuclease).
- Removal of the defective piece of DNA.
- Filling of the resulting gap by DNA polymerase.
- Sealing of the strand by DNA ligase.
Clinical Correlation:
Xeroderma Pigmentosum (XP) is a rare autosomal recessive disorder caused by defective NER. Affected individuals are extremely sensitive to sunlight and have a high risk of developing skin cancer due to failure to repair UV-induced DNA damage.
3. Mismatch Repair (MMR):
Despite high fidelity in DNA replication, occasional base mismatches occur, such as the insertion of cytosine instead of thymine opposite adenine. Mismatch Repair corrects these single-base errors immediately after replication.
Mechanism:
- The parental (template) DNA strand is methylated, while the newly synthesized strand is not.
- This methylation difference helps the repair system identify and correct the newly synthesized (incorrect) strand.
- The enzyme GATC endonuclease cuts the defective strand at a nearby methylated GATC sequence.
- An exonuclease removes the defective segment.
- DNA polymerase synthesizes the correct sequence, and DNA ligase seals the final nick.
Clinical Correlation:
Hereditary Nonpolyposis Colon Cancer (HNPCC), one of the most common inherited cancers, is caused by mutations in genes involved in mismatch repair, leading to accumulation of replication errors and genomic instability.
4. Double-Strand Break Repair (DSBR):
Double-Strand Breaks (DSBs) are among the most severe types of DNA damage. If left unrepaired, they can result in chromosomal fragmentation, translocations, and cell death.
Types of DSBR:
- Homologous Recombination (HR): Uses a homologous DNA sequence (usually a sister chromatid) as a template for error-free repair. Common in yeast and dividing cells.
- Non-Homologous End Joining (NHEJ): Joins broken DNA ends directly without a template. It is an error-prone process but predominant in mammalian cells.
Significance:
- Prevents chromosomal breakage and rearrangement.
- Maintains genome stability and prevents cell death.
Summary Table: DNA Repair Mechanisms
| Type of Repair | Mechanism | Key Enzymes | Example / Clinical Link |
|---|---|---|---|
| Base Excision Repair (BER) | Removes abnormal bases (e.g., uracil, xanthine) | Uracil DNA glycosylase, Endonuclease, DNA polymerase, DNA ligase | Deamination correction (C → U) |
| Nucleotide Excision Repair (NER) | Removes bulky DNA lesions and cross-links | Exinuclease, DNA polymerase, DNA ligase | Xeroderma Pigmentosum |
| Mismatch Repair (MMR) | Corrects base mispairing after replication | GATC endonuclease, Exonuclease, DNA polymerase, DNA ligase | HNPCC (Colon Cancer) |
| Double-Strand Break Repair (DSBR) | Repairs DNA double-strand breaks | Recombinase enzymes, Ligase | Homologous recombination, NHEJ |
Detailed Notes:
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