COMPLEMENTATION OF MISMATCH REPAIR GENE DEFECTS BY CHROMOSOME TRANSFER

The study of the multiple functions of mismatch repair genes in humans is being facilitated by the use of human tumor cell lines carrying de fined MMR gene mutations. Such cell Lines have elevated spontaneous mu tation rates and may accumulate mutations in other genes, some of whic h could be causally related to the phenotypes of these cells. One appr oach to establish a cause-effect relationship between a MMR gene defec t and a phenotype is to determine if that phenotype is reversed when a normal chromosome carrying a wild-type MMR gene is introduced by micr ocell fusion. This approach has the advantage of presenting the gene i n its natural chromosomal environment with normal regulatory controls and at a reasonable dosage. The approach also limits candidate genes t o only those encoded by the introduced chromosome and not elsewhere in the genome. Here we review studies demonstrating that hMSH2, hMSH3, h MSH6 and hMLH1 gene defects can each be complemented by transferring h uman chromosome 2, 5, 2 or 3, respectively. These transfers restore MM R activity, sensitivity to killings by MNNG, stability to microsatelli te sequences and low spontaneous HPRT gene mutation rates. (C) 1998 El sevier Science B,V. All rights reserved.