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J Biol Chem, Vol. 275, Issue 9, 6447-6452, March 3, 2000

The Human 20-kDa 5'-(CGG)_n-3'-binding Protein Is Targeted to the Nucleus and Affects the Activity of the FMR1 Promoter^*

Herbert Müller-Hartmann, Heidrun Deissler, Frauke Naumann, Birgit Schmitz, Jörg Schröer, and Walter Doerfler

From the Institute of Genetics, University of Cologne, Weyertal 121, D-50931 Koeln, Germany

Previous reports have described the human DNA CGG repeat-binding protein (CGGBP1 or p20), which binds specifically to nonmethylated, but not to methylated, 5'-(CGG)_n-3' repeats in the promoter of the fragile X mental retardation 1 (FMR1) gene. The results of transfection experiments into human HeLa cells using a p20-green fluorescent protein fusion construct indicate that the p20 protein is targeted to the nucleus. By deletion analyses, a nuclear localization signal has been found between amino acids 80 and 84. Deletions between amino acids 69 and 71 and between 95 and 167 interfere with 5'-(CGG)_n-3' binding. The results of electrophoretic mobility shift assays using DNA with 5'-(CGG)_n-3' repeats of different lengths render it likely that oligomers of the p20 protein bind to the repeat. In cotransfection experiments, the activity of the FMR1 promoter is reduced by the presence of p20. Upon transfection of the p20 cDNA construct into HeLa cells, transcription of the endogenous FMR1 gene is decreased. The green fluorescent protein-p20 fusion protein associates preferentially with the telomeres of the short arms of human chromosomes 13, 14, 15, 21, and 22. Their telomeres carry the genes for the 28 S rRNA, which contain 5'-(CGG)_n-3' repeats. The translated region of the p20 gene from three healthy, five fragile X syndrome, and five premutation-carrying individuals has been sequenced, but mutations have not been detected.

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^* This research was supported by the Center for Molecular Medicine Koeln TP13 and by the Kaempgen Stiftung Koeln.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EMBL Data Bank with accession number(s) AF094481.

To whom correspondence should be addressed. Tel.: 49-221-470-2386; Fax: 49-221-470-5163; E-mail: doerfler@scan.genetik.uni-koeln.de.

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Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.

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