Identification of mismatch repair genes and their role in the development of cancer.

Mismatched base pairs are generated by damage to DNA, by damage to nucleotide precursors, by errors that occur during DNA replication, and during the formation of intermediates in genetic recombination. Enzyme systems that faithfully repair these DNA aberrations have been identified in a wide variety of organisms. At lease some of the components of these repair systems have been conserved, both structurally and functionally, throughout evolutionary time. In humans, defective mismatch repair genes have been linked to hereditary nonpolyposis colon cancer as well as to sporadic cancers that exhibit length polmorphisms in simple repeat (microsatellite) DNA sequences. The involvement of mismatch repair defects in microsatellite instability and tumorigenesis suggests that a generalized mutator phenotype is responsible for the large number of genetic alterations observed in tumors.