ISOLATION AND CHARACTERIZATION OF THE 5' REGION OF THE HUMAN MISMATCHREPAIR GENE HPMS1

The hPMS1 gene encodes a mutL homolog that is implicated in DNA mismat ch repair and was found to be mutated in the germline of a patient wit h hereditary nonpolyposis colorectal cancer (HNPCC). To understand tra nscriptional regulation and to perform mutational analysis in the prom oter region, we cloned and characterized the genomic sequence of the 5 ' region of the gene. hPMS1 has an intron upstream of the initiation c odon. There were several transcripts with alternative splicing sites a nd multiple transcriptional start sites. The cloned 1.4-kbp fragment o f the 5' region contains a CpG island but no TATA-boxes, typical for p romoters of housekeeping genes. The promoter activity of the fragment was almost equal to that of the SV40 early promoter. Deletion analysis showed that about a 300-bp region was sufficient to initiate transcri ption. Although we searched for mutations in the hPMS1 promoter region in HNPCC kindreds, neither germline nor somatic mutations mere detect ed. However, we found a highly informative polymorphism in the first e xon that is useful for searching allelic losses because no polymorphic changes in hPMS1 have been reported previously. (C) 1998 Academic Pre ss.