Recognition of DNA alterations by the mismatch repair system

Misincorporation of non-complementary bases by DNA polymerases is a major s ource of the occurrence of promutagenic base-pairing errors during DNA repl ication or repair. Base-base mismatches or loops of extra bases can arise w hich, if left unrepaired, will generate point or frameshift mutations respe ctively. To counteract this mutagenic potential, organisms have developed a number of elaborate surveillance and repair strategies which co-operate to maintain the integrity of their genomes. An important replication-associat ed correction function is provided by the post-replicative mismatch repair system. This system is highly conserved among species and appears to be the major pathway for strand-specific elimination of base-base mispairs and sh ort insertion/deletion loops (IDLs), not only during DNA replication, but a lso in intermediates of homologous recombination. The efficiency of repair of different base-pairing errors in the DNA varies, and appears to depend o n multiple factors, such as the physical structure of the mismatch and sequ ence context effects. These structural aspects of mismatch repair are poorl y understood. In contrast, remarkable progress in understanding the biochem ical role of error-recognition proteins has been made in the recent past. I n eukaryotes, two heterodimers consisting of MutS-homologous proteins have been shown to share the function of mismatch recognition in vivo and in vit ro. A first MutS homologue, MSH2, is present in both heterodimers, and the specificity for mismatch recognition is dictated by its association with ei ther of two other MutS homologues: MSH6 for recognition of base-base mismat ches and small IDLs, or MSH3 for recognition of IDLs only. Mismatch repair deficiency in cells can arise through mutation, transcriptional silencing o r as a result of imbalanced expression of these genes.