U01.01.007 DNA repair

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Learning Objectives

  • Differentiate between single-strand and double-strand DNA repair pathways.
  • Identify the key enzymes involved in Base Excision Repair (BER) and Nucleotide Excision Repair (NER).
  • Correlate DNA repair defects with clinical syndromes like Xeroderma Pigmentosum and Lynch Syndrome.
  • Master the timing of repair mechanisms within the cell cycle.

1. Single-Strand Repair

These pathways address damage on one strand using the complementary strand as a template.

Nucleotide Excision Repair (NER)

  • Mechanism: Specific endonucleases remove bulky, helix-distorting lesions (e.g., pyrimidine dimers).
  • Timing: Occurs in the G1 phase.
  • Clinical: Defective in Xeroderma Pigmentosum (UV sensitivity, skin cancer).

Base Excision Repair (BER)

  • Mechanism: “GEL Please” — Glycosylase (removes base), Endonuclease (cleaves 5′), Lyase (cleaves 3′), Polymerase-β, and Ligase.
  • Function: Repairs spontaneous/toxic deamination.
  • Timing: Occurs throughout the cell cycle.

Mismatch Repair

  • Mechanism: Removes mismatched nucleotides in the newly synthesized strand.
  • Timing: Predominantly in S phase.
  • Clinical: Defective in Lynch Syndrome (HNPCC).

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2. Double-Strand Repair

Required when both strands of the DNA helix are severed, posing a high risk for chromosomal instability.

Mechanism Requirement Accuracy & Clinical Notes
Nonhomologous End Joining (NHEJ) None (rejoins 2 ends) Error-prone; DNA may be lost or translocated.
Homologous Recombination Homologous duplex template Accurate; no loss of nucleotides. Defective in BRCA1/2 mutations (Breast/Ovarian cancer).

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3. Clinical Mnemonic & Summary

“GEL Please” for Base Excision Repair:
1. Glycosylase (removes base/creates AP site)
2. Endonuclease (cleaves 5′ end)
3. Lyase (cleaves 3′ end)
4. Polymerase-β (fills gap)
5. Ligase (seals gap)

 

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