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J. Biol. Chem., Vol. 279, Issue 37, 38313-38324, September 10, 2004

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The Tumor Suppressor Gene HIC1 (Hypermethylated in Cancer 1) Is a Sequence-specific Transcriptional Repressor

DEFINITION OF ITS CONSENSUS BINDING SEQUENCE AND ANALYSIS OF ITS DNA BINDING AND REPRESSIVE PROPERTIES^*

Sébastien Pinte, Nicolas Stankovic-Valentin, Sophie Deltour, Brian R. Rood¶, Cateline Guérardel, and Dominique Leprince||

From the CNRS UMR 8526, Institut de Biologie de Lille, Institut Pasteur de Lille, 1 Rue Calmette, Lille Cedex 59017, France, and the ^¶Division of Pediatric Hematology/Oncology, Children's National Medical Center, Washington, D. C. 20010

HIC1 (hypermethylated in cancer 1) is a tumor suppressor gene located at chromosome 17p13.3, a region frequently hypermethylated or deleted in human tumors and in a contiguous-gene syndrome, the Miller-Dieker syndrome. HIC1 is a transcriptional repressor containing five Krüppel-like C₂H₂ zinc fingers and an N-terminal dimerization and autonomous repression domain called BTB/POZ. Although some of the HIC1 transcriptional repression mechanisms have been recently deciphered, target genes are still to be discovered. In this study, we determined the consensus binding sequence for HIC1 and investigated its DNA binding properties. Using a selection and amplification of binding sites technique, we identified the sequence 5'-^C/_GNG^C/_GGGGCA^C/_A CC-3' as an optimal binding site. In silico and functional analyses fully validated this consensus and highlighted a GGCA core motif bound by zinc fingers 3 and 4. The BTB/POZ domain inhibits the binding of HIC1 to a single site but mediates cooperative binding to a probe containing five concatemerized binding sites, a property shared by other BTB/POZ proteins. Finally, full-length HIC1 proteins transiently expressed in RK13 cells and more importantly, endogenous HIC1 proteins from the DAOY medulloblastoma cell line, repress the transcription of a reporter gene through their direct binding to these sites, as confirmed by chromatin immunoprecipitation experiments. The definition of the HIC1-specific DNA binding sequence as well as the requirement for multiple sites for optimal binding of the full-length protein are mandatory prerequisites for the identification and analyses of bona fide HIC1 target genes.

Received for publication, February 13, 2004 , and in revised form, June 8, 2004.

^* This work was supported by funds from CNRS, the Pasteur Institute, and the Association pour la Recherche contre le Cancer. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Present address: Welcome Trust, University of Cambridge, Cambridge, United Kingdom.

^|| To whom correspondence should be addressed. Tel.: 33-3-2087-1119; Fax: 33-3-2087-1111; E-mail: dominique.leprince{at}ibl.fr.

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