Mismatches, or non-Watson–Crick base pairs in a DNA duplex, can arise through the following processes:

1. Replication Errors;

2. Deamination of 5-methylcytosine in DNA to yield thymine; and

3. Recombination between DNA strands that are not completely homologous.

The repair of replication errors is the best understood system. If DNA polymerase introduces an incorrect nucleotide and it is not corrected by 3' exonucleolytic proofreading activity of the enzyme (see here), the fully replicated DNA will contain a mismatch at that site. The error can be corrected by the process called mismatch repair.

In E. coli the proteins that participate in mismatch repair include the products of genes mutH, mutL, and mutS. Another required gene product has been identified as DNA helicase II. The E. coli single-stranded binding protein also appears to be involved.

The prokaryotic mismatch correction system works by "scanning" newly replicated DNA, looking for both mismatched bases and single-base insertions or deletions. When it finds a problem, part of one strand containing the mismatched region is cut out and replaced (Figure 25.16).

The mismatch repair system must reliably recognize the proper strand to repair, for if it chose randomly, it would be incorrect half the time and there would be no gain in replication accuracy. Mismatch repair enzymes can identify the newly replicated strand because it is unmethylated for a short period of time after replication. Only later, after the replication fork passes, is the DNA methylation completed. Thus, the parental strand is the methylated one. E. coli methylates primarily at the 'A' of the sequence GATC. As a result, recognition of an unmethylated GATC as far as 1 kbp or more away from the GATC site, in either direction, can help a cell identify which one is the newly replicated strand. After the methylation system has acted on all GATC sites in the daughter strand, it is too late for the mismatch repair system to recognize the more recently synthesized DNA strand, and thus cannot improve total DNA replication fidelity. However, by operating before methylation, the mismatch repair system increases overall replication fidelity by about 100-fold-from about 1 error in 10⁸ base pairs replicated to about 1 in 10¹⁰.

1. DNA Repair

2. Mutations