Mismatch-repair

A mismatch is a base pairing error in the DNA - e.g. G-T or A-C instead of the correct G-C or A-T. Such errors occasionally occur during DNA replication despite the high accuracy of DNA polymerase.

The mismatch repair system is an evolutionarily conserved system that is essential for the maintenance of cellular DNA. The mismatch repair system recognizes mismatched bases that occur during DNA replication or through spontaneous deamination (mismatch) and corrects them. This process is particularly important for maintaining genetic stability and preventing mutations, e.g. in the formation of malignant tumors. The mismatch repair system includes key proteins such as PMS2 (postmeiotic segregation increased 2) and MSH6 (MutS homolog 6). It has been hypothesized that the presence of a large number of neoantigens in MMR-deficient tumors accounts for their response to immune checkpoint inhibitor therapy (Hempel C et al. 2025).

Remark: MMR-deficient tumors (dMMR or MSI-H) are characterized by a high mutation rate, especially in short repetitive DNA sequences (microsatellites). These tumors often respond well to immune checkpoint inhibitors (e.g. pembrolizumab).

Main functions of the MMR system (see illustration)

• Recognition of mismatches (e.g. G-T, A-C)
• Differentiation between new and old DNA strand
• Cutting out the error together with the surrounding section
• Re-synthesis of the correct sequence

Sequence of mismatch repair (in E. coli, similar in eukaryotes with homologous proteins)

Step 1: Recognition of the mismatch

• The MutS protein (in E. coli) recognizes the mismatch in the DNA.
• MutS forms a complex with MutL to start the repair process.

Step 2: Identification of the "wrong" strand

• The system must distinguish the newly synthesized strand (which contains the error) from the original strand.
• In bacteria, this is done by methylation: only the old strand is methylated directly after replication (at GATC sites, by Dam methylase).
• MutH recognizes the non-methylated (new) side and cuts there.

Step 3: Removal of the defective section

• After the cut by MutH, the strand is degraded by exonucleases in the direction of the error.
• The single-stranded region is unwound by helicase (e.g. UvrD)

Step 4: New synthesis

• The resulting gap is filled with the correct sequence by DNA polymerase III (in E. coli).
• DNA ligase closes the remaining single strand break.

Mismatch repair in eukaryotes

• Homologous proteins: MSH2-MSH6 (analogous to MutS), MLH1-PMS2 (analogous to MutL)
• Eukaryotes do not use methylation, but rely on Okazaki fragments, gaps or the replication machinery to differentiate strands.

The mismatch repair system is an important mechanism that contributes to the maintenance of genomic integrity. It is involved in mitotic and meiotic recombination, apoptosis, immunoglobulin gene rearrangement, somatic hypermutation and other processes. Deficits in mismatch repair lead to hypermutability and the phenomenon of microsatellite instability, a form of genome instability. The detection of a deficient mismatch repair function or microsatellite instability is used for diagnostic, predictive and prognostic purposes.

Mutations in MMR genes (e.g. MLH1, MSH2, MSH6, PMS2) are associated with hereditary tumor entities, e.g. colorectal cancer (especially Lynch syndrome), constitutional mismatch repair deficiency syndrome, endometrial carcinoma or gastric carcinoma.

Basically, information on mismatch repair functions leads to a better understanding of which tumor entities could take a more aggressive clinical course.

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