In-Depth Notes on DNA Repair Mechanisms

DNA Repair Mechanisms

Overview of DNA Repair

• Importance of DNA Repair

  • Corrects errors that occur during DNA replication.
  • Protects the integrity of genetic information.
  • Redundant systems enhance repair efficiency.

• Proofreading by DNA Polymerase

  • Removes mismatched bases during replication to prevent mutations.

General Themes in DNA Repair

• Usually Targets Double-Stranded DNA
  • Most repair mechanisms focus on correcting errors in double-stranded DNA.
• Template Requirement
  • Repair processes rely on an existing template for accurate correction of nucleotides.
• Redundant Systems
  • Multiple pathways exist to ensure DNA repair, emphasizing its importance.

Types of DNA Repair

1. Single-Strand Damage Repair:

   • Mismatch Repair (MMR)
   • Direct Repair (DR)
   • Base-Excision Repair (BER)
   • Nucleotide-Excision Repair (NER)

2. Double-Strand Break Repair:

   • Homology-Directed Repair (HDR)
   • Nonhomologous End Joining (NHEJ)

Mismatch Repair (MMR)

• Mechanism:
  • Identifies and corrects mismatched bases after DNA replication.
  • Methylation at GATC sequences allows differentiation of old vs. new strands.
• Process Summary:
  1. Mismatch-repair complex recognizes the mismatch.
  2. Exonucleases remove mismatched nucleotides starting from GATC.
  3. DNA polymerase replaces the removed nucleotides.
  4. DNA ligase seals the nicks in the sugar-phosphate backbone.
• Human Relevance:
  • Mutations in MMR genes increase susceptibility to diseases like colon cancer.

Direct Repair (DR)

• Definition:
  • Mechanisms that revert altered nucleotides to their correct structures.
• Key Note:
  • Humans do not possess the enzyme photolyase, crucial for direct repair in other organisms.

Base-Excision Repair (BER)

• Purpose:
  • Repairs small, non-helix-distorting base lesions.
• Mechanism:
  1. DNA glycosylases recognize and remove a specific damaged base, generating an AP site.
  2. AP endonuclease cleaves the DNA strand around the AP site and removes the deoxyribose sugar.
  3. DNA polymerase adds new nucleotides to the exposed 3'-OH group.
  4. DNA ligase seals the gap, restoring the original sequence.

Nucleotide-Excision Repair (NER)

• Purpose:
  • Removes and repairs bulky lesions that distort the DNA helix.
• Process Summary:
  1. Damage recognition leading to strand separation.
  2. Cleavage of the strand at both sides of the damaged segment.
  3. Removal of the damaged section followed by DNA synthesis to fill the gap.
  4. Sealing by DNA ligase.
• Condition Association:
  • Defective NER leads to Xeroderma Pigmentosum, increasing skin cancer risk due to uncorrected thymine dimers.

Double-Strand Break Repair

1. Homology-Directed Repair
   • Utilizes a homologous DNA sequence as a template for repair.
2. Nonhomologous End Joining (NHEJ)
   • Directly joins the ends of broken DNA strands without a template.
   • Mechanism involves proteins like KU70/KU80, DNA-PKcs, and MRN for recognition and processing of DNA ends.

Repair System Summary Table