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Molecular and Cellular Biology, November 2003, p. 7992-8007, Vol. 23, No. 22
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.22.7992-8007.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Regulation of the Human MSH6 Gene by the Sp1 Transcription Factor and Alteration of Promoter Activity and Expression by Polymorphisms

Isabella Gazzoli1 and Richard D. Kolodner1,2,3

Ludwig Institute for Cancer Research,1 Department of Medicine,2 Department of Cellular and Molecular Medicine and Cancer Center, University of California San Diego School of Medicine, La Jolla, California 920933

Received 27 February 2003/ Returned for modification 15 April 2003/ Accepted 5 August 2003

Defects in human DNA mismatch repair have been reported to underlie a variety of hereditary and sporadic cancer cases. We characterized the structure of the MSH6 promoter region to examine the mechanisms of transcriptional regulation of the MSH6 gene. The 5'-flanking region of the MSH6 gene was found to contain seven functional Sp1 transcription factor binding sites that each bind Sp1 and Sp3 and contribute to promoter activity. Transcription did not appear to require a TATA box and resulted in multiple start sites, including two major start sites and at least nine minor start sites. Three common polymorphisms were identified in the promoter region (-557 T->G, -448 G->A, and -159 C->T): the latter two were always associated, and each of these functionally inactivated a different Sp1 site. The polymorphic allele -448 A -159 T was demonstrated to be a common Caucasian polymorphism found in 16% of Caucasians and resulted in a five-Sp1-site promoter that had 50% less promoter activity and was more sensitive to inactivation by DNA methylation than the more common seven Sp1 site promoter allele, which was only partially inactivated by DNA methylation. In cell lines, this five-Sp1-site polymorphism resulted in reduced MSH6 expression at both the mRNA and protein level. An additional 2% of Caucasians contained another polymorphism, -210 C->T, which inactivated a single Sp1 site that also contributes to promoter activity.

* Corresponding author. Mailing address: Ludwig Institute for Cancer Research, UCSD School of Medicine-CMME 3058, 9500 Gilman Dr., La Jolla, CA 92093-0669. Phone: (858) 534-7802. Fax: (858) 534-7750. E-mail: igazzoli{at}ucsd.edu.

Molecular and Cellular Biology, November 2003, p. 7992-8007, Vol. 23, No. 22
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.22.7992-8007.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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