The multifaceted mismatch-repair system

Abstract

The mismatch repair (MMR) system is one of the most important guardians of genomic integrity. It improves the fidelity of DNA replication, aborts illegitimate recombination and affects the outcome of several other processes of DNA metabolism. The malfunction of MMR gives rise to a mutator phenotype and microsatellite instability. MMR defects in humans lead to cancer of the colon, endometrium and ovary. In mice, the predominant malignancies are lymphomas and late-onset gastrointestinal tumours. The MMR process involves a complex interplay of MMR-specific proteins with the replication and/or recombination machinery. It is activated by the binding of the mismatch-recognition factors, MutSα and MutSβ, to substrates that contain base?base mismatches and insertion/deletion loops that arise during recombination or from errors of DNA polymerases. The ATP-dependent recruitment of MutL homologues to the mismatch-bound complex is followed by the exonuclease-mediated degradation of the error-containing strand. Once the mismatch had been removed, resynthesis of the degraded region by a DNA polymerase, followed by sealing of the remaining nick by DNA ligase, completes the repair process. MMR proteins play an important role in DNA-damage processing and signalling. MMR-deficient cells are resistant to death that is induced by several important chemotherapeutic agents. In recent years, the MMR system has emerged as a modifier of enigmatic processes of DNA metabolism such as somatic hypermutation, class-switch recombination and triplet-repeat expansion. The role of MMR proteins in these processes remains obscure.