EDITING DNA-REPLICATION AND RECOMBINATION BY MISMATCH REPAIR - FROM BACTERIAL GENETICS TO MECHANISMS OF PREDISPOSITION TO CANCER IN HUMANS

A hereditary form of colon cancer, hereditary non-polyposis colon canc er (HNPCC), is characterized by high instability of short repeated seq uences known as microsatellites. Because the genes controlling microsa tellite stability were known in bacteria and yeast, as was their evolu tionary conservation, the search for human genes responsible for HNPCC became a 'targeted' search for known sequences. Mismatch-repair defic iency in bacteria and yeast produces multiple phenotypes as a result o f its dual involvement in the editing of both replication errors and r ecombination intermediates. In addition, mismatch-repair functions are specialized in eukaryotes, characterized by specific mitotic (versus meiotic) functions, and nuclear (versus mitochondrial) localization. G iven the number of phenotypes observed so far, we predict other links between mismatch-repair deficiency and human genetic disorders. For ex ample, a similar type of sequence instability has been found in HNPCC tumours and in a number of neuro-muscular genetic disorders. Several h uman mitochondrial disorders display genomic instabilities reminiscent of yeast mitochondrial mismatch-repair mutants. In general, the proce ss of mismatch repair is responsible for the constant maintenance of g enome stability and its faithful transmission from one generation to t he next. However, without genetic alteration, species would not be. ab le to adapt to changing environments. It appears that nature has devel oped both negative and positive controls for genetic diversity. In bac teria, for example, an inducible system (sos) exists which generates g enetic alterations in response to environmental stress (e.g. radiation , chemicals, starvation). Hence, the cost of generating diversity to a dapt to changing conditions might be paid as sporadic gene alterations associated with disease.