In Lynch syndrome, the mismatch repair (MMR) protein MSH2 is lost due to a germline mutation. Which downstream molecular consequence most directly accounts for the microsatellite instability (MSI-H) phenotype?

• A Impaired MutL homolog cleavage of oxidized guanine bases
• B Defective base-excision repair of uracil mismatches
• C Failure to form MSH2-MSH6 heterodimer required to recognize mononucleotide insertion-deletion loops ✓
• D Loss of MSH2 co-activator function for ATM kinase activation

Explanation

MSH2 heterodimerizes with MSH6 (forming MutSα) to recognize small insertion-deletion loops and single base mismatches generated during DNA replication slippage at microsatellite repeats. Without this recognition complex, replication errors at microsatellites are not corrected, generating MSI-H. Base-excision repair handles oxidized bases and uracil via OGG1 and UNG respectively; ATM co-activation is unrelated to MMR.

Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

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