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Molecular and Cellular Biology, February 2001, p. 928-939, Vol. 21, No. 3
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.3.928-939.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Sequence-Specific Transcriptional Repression by KS1, a Multiple-Zinc-Finger-Krüppel-Associated Box Protein

Brian Gebelein1,dagger and Raul Urrutia*,1,2,3

Department of Molecular Neuroscience,1 Department of Biochemistry and Molecular Biology,2 and Gastroenterology Research Unit,3 Mayo Clinic, Rochester, Minnesota 55905

Received 27 July 2000/Returned for modification 7 September 2000/Accepted 20 October 2000

The vertebrate genome contains a large number of Krüppel-associated box-zinc finger genes that encode 10 or more C2-H2 zinc finger motifs. Members of this gene family have been proposed to function as transcription factors by binding DNA through their zinc finger region and repressing gene expression via the KRAB domain. To date, however, no Krüppel-associated box-zinc finger protein (KRAB-ZFP) and few proteins with 10 or more zinc finger motifs have been shown to bind DNA in a sequence-specific manner. Our laboratory has recently identified KS1, a member of the KRAB-ZFP family that contains 10 different C2-H2 zinc finger motifs, 9 clustered at the C terminus with an additional zinc finger separated by a short linker region. In this study, we used a random oligonucleotide binding assay to identify a 27-bp KS1 binding element (KBE). Reporter assays demonstrate that KS1 represses the expression of promoters containing this DNA sequence. Deletion and site-directed mutagenesis reveal that KS1 requires nine C-terminal zinc fingers and the KRAB domain for transcriptional repression through the KBE site, whereas the isolated zinc finger and linker region are dispensable for this function. Additional biochemical assays demonstrate that the KS1 KRAB domain interacts with the KAP-1 corepressor, and mutations that abolish this interaction alleviate KS1-mediated transcriptional repression. Thus, this study provides the first direct evidence that a KRAB-ZFP binds DNA to regulate gene expression and provides insight into the mechanisms used by multiple-zinc-finger proteins to recognize DNA sequences.

* Corresponding author. Mailing address: Gastroenterology Research Unit, 2-445 Alfred Bldg., Saint Marys Hospital, Rochester, MN 55905. Phone: (507) 284-7500. Fax: (507) 255-6318. E-mail: urrutia.raul{at}mayo.edu.

dagger Present address: Columbia University, New York, NY 10032.

Molecular and Cellular Biology, February 2001, p. 928-939, Vol. 21, No. 3
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.3.928-939.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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