MismatchReparaturdefekte

Mismatch repair (MMR) is a conserved DNA repair pathway that corrects base-base mismatches and small insertion–deletion loops that arise during DNA replication and recombination. By correcting these errors, MMR helps maintain genomic stability and reduces the mutation rate in cells.

In bacteria, the pathway typically begins with MutS recognizing a mismatch and recruiting MutL. MutH then introduces a nick on the newly synthesized strand at hemimethylated GATC sites, providing an entry point for exonucleases to remove the error-containing segment. DNA polymerase fills the gap and DNA ligase seals the strand. The system relies on strand discrimination to ensure the correct (new) strand is repaired.

In eukaryotes, the MMR system uses MutS homologs that form two primary complexes: MutSα (MSH2–MSH6) and MutSβ (MSH2–MSH3), which detect base-pair mismatches and small insertion–deletion loops. Repaired strands are coordinated by MutL homologs, primarily MutLα (MLH1–PMS2) in humans, with MutLβ (MLH1–MLH3) playing supporting roles. Exonuclease 1 (EXO1) and other nucleases excise the erroneous DNA, while DNA polymerases fill in the gap and ligases seal the strand. Accessory factors such as PCNA, RFC, and RPA help direct the process and maintain replication coordination.

Clinical significance is substantial. Defects in MMR cause microsatellite instability and a high mutational burden, contributing to Lynch syndrome (hereditary nonpolyposis colorectal cancer) and various sporadic cancers. MMR status informs prognosis and treatment, including the use of certain immunotherapies in tumors with MMR deficiency or microsatellite instability.