Eukaryotic Mismatch Repair

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 segments that are not completely homologous.

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

E. coli proteins that participate in mismatch repair include the products of genes mutH, mutL, and mutS.

A similar repair system operates in eukaryotic cells involving three proteins related to MutS (called MSH2, MSH3, and MSH6). Combinations of the proteins dimerize and work on specific mismatches. Several homologs of MutL are known in eukaryotic cells, but no analog is known for MutH. It is not known in eukaryotic systems how the newly replicated strand is recognized because selective methylation does not appear to be involved. Mutations in the genes that control mismatch repair cause cells to have a higher than normal mutation rate (mutator phenotype) and are associated with a greater tendency to form tumors.

Mutations in mismatch repair genes have been identified in individuals with an inherited cancer predisposition called HNPCC (heritable non-polyposis colon cancer). Tumor cells from HNPCC patients exhibit a phenomenon called microsatellite instability. DNA in these cells contain a large number of mutations in regions of the genome containing repeats of single-, double-, and triple-nucleotide sequences. The mutatations usually create large increases in the number of repeating units in such sequences. These data suggest that the product and template strands normally "slip" at such sites so that DNA polymerase copies a short repeating sequence more than once, or else skips a segment. The heteroduplex arising from such a slippage would normally be corrected by mismatch repair, but cells from these individuals are unable to do so.

See also: Prokaryotic Mismatch Repair, Postreplication Repair

INTERNET LINKS:

> 1. DNA Repair

> 2. Mutations