A somatic mutation in the mismatch repair gene MLH1 leads to microsatellite instability (MSI) in a colon cancer patient. Lynch syndrome (hereditary) involves germline MMR mutations. Mismatch repair corrects base mismatches and insertion-deletion loops after replication. Which strand is recognized as the 'parental' strand to direct MMR to correct the newly synthesized strand in eukaryotes?

• A The strand with a nick or gap left by the discontinuous lagging strand synthesis
• B The strand associated with PCNA (proliferating cell nuclear antigen) via strand discontinuities ✓
• C The strand with N6-methyladenine (m6A) marks as in bacteria (Dam methylase)
• D The strand identified by the direction of replication fork movement (3' to 5' strand)

Explanation

Unlike bacteria, which use Dam methylation of adenine (GATC sequences) to distinguish old strand from new strand in mismatch repair, eukaryotes lack this methylation system for strand discrimination. In eukaryotic MMR, strand discrimination relies on the presence of a nick or gap (strand discontinuity) in the newly synthesized strand. Okazaki fragments on the lagging strand and nicks/gaps on the leading strand serve as strand discrimination signals. PCNA (the DNA sliding clamp) is loaded at these discontinuities and interacts with MSH6/MSH3 and MLH1/PMS2 to direct excision to the newly synthesized (error-containing) strand rather than the parental strand. This PCNA-mediated mechanism ensures that the parental template strand is preserved during repair.

Reference: Harper's Illustrated Biochemistry, 32nd ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.