Mismatch repair and cancer

Abstract

A common form of human malignancy, hereditary non-polyposis colorectal cancer (HNPCC), as well as some sporadic human cancers, has been shown to exhibit frequent alterations in microsatellite sequences. This phenotype was ascribed to a defect in replication error correction, and indeed several tumour derived cell lines are deficient in mismatch repair. To date, four HNPCC loci, on chromosomes 2p, 2q, 3p and 7q, have been linked with genes designated hMSH2, hPMS1, hMLH1 and hPMS2, respectively, which encode proteins that display an extensive degree of sequence similarity to polypeptides involved in postreplicative mismatch correction in Escherichia coli and Saccharomyces cerevisiae. We have recently identified a new protein, GTBP, that is essential for mismatch repair in human cells. GTBP mutations are not associated with the profound MI commonly encountered in hereditary colon cancers. The roles of the proteins encoded by the individual mismatch repair genes in postreplicative mismatch correction and genome instability are discussed, with a view to assessing the potential utility of these findings in diagnosis of cancer predisposition and therapy.