DNA repair

Single-Strand Repair

• Nucleotide Excision Repair (NER) t
  • Fixes: Bulky lesions (thymine dimers from UV light).
  • Mechanism: An excinuclease complex identifies the distortion, cleaves the phosphodiester backbone on both sides of the lesion, and removes the damaged segment. DNA Polymerase fills the gap, and DNA Ligase seals it.
  • Defect: Xeroderma Pigmentosum (↑ skin cancer risk).
• Base Excision Repair (BER)
  • Fixes: Spontaneous/toxic deamination (e.g., C→U).
  • Key Enzyme: Glycosylase.
  • Mechanism:
    1. Base-specific Glycosylase removes the altered base, creating an apurinic/apyrimidinic (AP) site.
    2. AP-Endonuclease cleaves the 5’ end.
    3. AP-Lyase (part of DNA Pol-beta) cleaves the 3’ end.
    4. DNA Polymerase fills the gap.
    5. DNA Ligase seals the nick.
  • Mnemonic: “GEL PLease” (Glycosylase, Endonuclease, Lyase, Polymerase, Ligase)
• Mismatch Repair (MMR)
  • Fixes: Errors during DNA replication.
  • Defect: Lynch Syndrome / HNPCC (↑ colorectal, endometrial, ovarian cancer risk).

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Double-Strand Break Repair

• Homologous Recombination (HR)
  • When: S, G2 phases (uses sister chromatid as template).
  • Quality: Accurate, high-fidelity repair.
  • Defect: BRCA1/BRCA2 mutations (↑ breast, ovarian, prostate cancer risk).
• Non-Homologous End Joining (NHEJ)
  • When: G1 phase (no template available).
  • Quality: Error-prone, can cause deletions/insertions.
  • Defect: Ataxia-Telangiectasia (mutation in ATM gene).

Exonuclease vs. Endonuclease

Feature	Exonuclease	Endonuclease
Action	Removes nucleotides from the ends (5’ or 3’) of a nucleic acid chain.	Cleaves phosphodiester bonds within a nucleic acid chain.
Products	Single mononucleotides, released one at a time.	Oligonucleotide fragments of varying sizes.
Specificity	Generally not sequence-specific.	Can be non-specific (e.g., DNase I) or highly sequence-specific (e.g., restriction enzymes).
Key Example	DNA Polymerase Proofreading: 3’→5’ exonuclease activity removes mismatched bases during replication.	Restriction Enzymes: Recognize and cut specific palindromic DNA sequences (e.g., for RFLP, cloning).
Circular DNA	Cannot act on circular DNA (no free ends).	Can act on circular DNA.

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