Mismatch repair in correction of replication errors and processing of DNA damage

The primary role of mismatch repair (MMR) is to maintain genomic stability by removing replication errors from DNA. This repair pathway was originally implicated in human cancer through an association between microsatellite i nstability in colorectal tumors in hereditary nonpolyposis colon cancer (HN PCC) kindreds. Microsatellites are short repetitive sequences which are oft en copied incorrectly by DNA polymerases because the template and daughter strands in these regions are particularly prone to misalignment. These repl ication-dependent events create loops of extrahelical bases which would pro duce frameshift mutations unless reversed by MMR. One consequence of MMR lo ss is a widespread expansion and contraction of these repeated sequences th at affects the whole genome. Defective MMR is therefore associated with a m utator phenotype. Since the same pathway is also responsible for repairing base:base mismatches, defective cells also experience large increases in th e frequency of spontaneous transition and transversion mutations. Three dif ferent approaches have been used to investigate the function of individual components of the MMR pathway. The first is based on the biochemical charac terization of the purified protein complexes using synthetic DNA substrates containing loops or single mismatches. In the second, the biological conse quences of MMR loss are inferred from the phenotype of cell lines establish ed from repair-deficient human tumors, from tolerant cells or from mice def ective in single MMR genes. In particular, molecular analysis of the mutati ons in endogenous or reporter genes helped to identify the DNA substrates f or MMR. Finally, mice bearing single inactive MMR genes have helped to defi ne the involvement of MMR in cancer prevention. (C) 2001 Wiley-Liss, Inc.