Mismatch repair

Mismatch Repair (MMR) - The DNA Proofreaders

• Function: A crucial post-replication repair system that corrects errors missed by DNA polymerase's proofreading activity.
• Mechanism: Identifies and repairs mismatched bases (e.g., G-T instead of G-C) and small insertions/deletions (indels) that arise during DNA replication.

identifying and correcting a base pair mismatch in a newly synthesized DNA strand)

⭐ Defective MMR is the genetic basis for Lynch syndrome, also known as Hereditary Non-Polyposis Colorectal Cancer (HNPCC), which leads to a high risk of colorectal, endometrial, and other cancers.

MMR Pathway - The Repair Crew

pathway diagram with MutS and MutL homologs)

• Recognition & Recruitment: MutS homologs (MSH2, MSH6) bind the mismatch. MutL homologs (MLH1, PMS2) are recruited.
• Strand Identification:
  • Prokaryotes: Parent strand is methylated (dam methylase); new strand is not.
  • Eukaryotes: New strand identified by nicks near the replication fork.
• Repair Execution: The complex nicks the new strand, an exonuclease removes the mismatched segment, DNA polymerase resynthesizes the gap, and DNA ligase seals the nick.

⭐ Lynch Syndrome (HNPCC): An autosomal dominant disease caused by inherited mutations in MMR genes (e.g., MSH2, MLH1), leading to microsatellite instability and a high risk of colorectal, endometrial, and other cancers.

Lynch Syndrome - When Repair Fails

• Inheritance: Autosomal dominant. A single mutated allele is sufficient to ↑ cancer risk.
• Genetic Basis: Germline mutations in DNA mismatch repair (MMR) genes. The most frequently affected are:
  • MLH1
  • MSH2
  • MSH6
  • PMS2
• Pathophysiology: Inactivation of the second MMR allele (two-hit hypothesis) leads to defective repair of DNA replication errors.
• Molecular Hallmark: Results in microsatellite instability (MSI), where short, repetitive DNA sequences vary in length due to faulty repair. This is a key feature in tumor analysis.

• Associated Cancers:
  • 📌 Mnemonic: CEO
  • Colorectal (often right-sided)
  • Endometrial (most common extra-colonic cancer)
  • Ovarian
  • Also stomach, small bowel, and urothelial cancers.

⭐ Lynch syndrome is also known as Hereditary Non-Polyposis Colorectal Cancer (HNPCC). Unlike FAP, it doesn't typically involve numerous polyps, but cancer develops at a much younger age.

High-Yield Points - ⚡ Biggest Takeaways

• Primary Function: Corrects errors made during DNA replication that escape the polymerase's proofreading function.
• Key Step: Differentiates between parent and daughter strands to repair the newly synthesized strand. In prokaryotes, this is guided by adenine methylation.
• Core Machinery: Involves MutS/MSH (mismatch recognition) and MutL/MLH (coordination) protein families.
• Clinical Significance: Inherited mutations in MSH2, MLH1, MSH6, PMS2 cause Lynch syndrome (HNPCC).
• Pathological Hallmark: Defective MMR results in microsatellite instability (MSI).