DNA Mismatch Repair

DNA mismatch repair (MMR) is a highly conserved biological pathway that is important in maintaining genomic stability. In a normal setting, MMR corrects base-base mismatches and insertion/deletion mispairs that occur during DNA replication and recombination, preventing mutations from becoming permanent in dividing cells.  Examples of mismatched bases include a G/T or A/C pairing. Mismatches are commonly due to tautomerization of bases during DNA replication. The damage is repaired by recognition of the error caused by the mismatch, determining the parent and daughter strand, and excising the wrongly incorporated base and replacing it with the correct nucleotide.

MMR also suppresses homologous recombination and plays a role in signaling of DNA damage. MMR defects lead to a range of genomic instabilities including predisposition to certain types of cancer and resistance to some chemotherapeutic agents.  The E. coliMMR pathway has been studied extensively, and several human MMR proteins have been identified based on their homology to E. coliMMR proteins.  Examples include:

MMR-deficient tumors have 10-100 times more mutations than tumors with intact MMR pathways. Mutations in at least five key human MMR genes (MSH2, MSH6, MLH1, PMS1, and PMS2) have been associated with colorectal cancers, and a recent report by investigators at Cancer Research UK described their study of numerous patients’ breast cancer tumors in which they detected an array of MMR-deficiencies (single base substitutions and small insertions/deletions) in a subset of those tumors.

Cancers deficient in MMR proteins contain exceptionally high numbers of somatic mutations which result in the expression of neoantigens.  In fact, MMR-deficient cancers, regardless of the cancers’ tissue of origin, have been responsive to immune therapies, such as PD-1 blocking antibodies, most likely because the large number of neoantigens present in MMR-deficient tumors makes them sensitive to immune checkpoint blockade therapy.