Mismatch Repair Genes

Abstract

The mismatch repair (MMR) system is necessary for the maintenance of genomic stability. The primary role of MMR is to correct errors such as base/base mismatches and small insertions/deletions that arise during DNA (deoxyribonucleic acid) synthesis. Loss of functional MMR results in increased rates of point mutations and microsatellite instability. Post‐replicative MMR is strand‐specific and serves mutation avoidance. Outside replication, discrimination between old and newly synthesised DNA strands is no longer necessary, and the MMR system can be mutagenic. Such non‐canonical actions of MMR are required, for example, for the generation of immunoglobulin diversity. The anti‐mutator and mutator activities of MMR play important roles in human diseases. Notably, germline mutations in MMR genes cause predisposition to Lynch syndrome, whereas epigenetic inactivation of the MMR gene MLH1 underlies 15% of sporadic colorectal and other cancers. Key Concepts Post‐replicative mismatch repair can counteract or promote mutations. DNA mismatch repair genes are conserved in evolution. DNA mismatch repair genes comply with Knudson's two‐hit paradigm for tumour suppressor genes. Deficient DNA mismatch repair is responsible for microsatellite instability in tumours. Inherited defects in DNA mismatch repair underlie Lynch syndrome, a dominant predisposition to colorectal, endometrial and other cancers.