DNA Mismatch Repair

DNA mismatch repair (MMR) is the cellular system that finds and corrects mispaired bases and small insertion or deletion loops left behind after DNA replication. It improves the accuracy of copying the genome by roughly a hundredfold beyond the proofreading of the polymerase itself.

Even with proofreading, DNA polymerase leaves about one mismatched base in every 10⁷ it inserts. Left alone, these would become permanent mutations in the next round of copying. Mismatch repair scans newly made DNA for distortions in the double helix and fixes them, bringing the final error rate down to about one in 10⁹ to 10¹⁰.

In Escherichia coli, the protein MutS recognizes a mismatch and recruits MutL, which activates the endonuclease MutH. MutH cuts the new strand, identified because it is not yet methylated at GATC sequences, and the faulty stretch is removed and resynthesized. Eukaryotes use related proteins, MSH2 with MSH6 or MSH3, and MLH1 with PMS2, and are thought to recognize the new strand by its nicks and by the replication machinery.

Inherited mutations in MMR genes cause Lynch syndrome, which carries a high risk of colorectal and other cancers. Tumors with defective repair show many errors in repetitive sequences, called microsatellite instability, and such tumors often respond well to immune checkpoint therapy. The pathway works alongside other forms of DNA repair.