tailieunhanh - Báo cáo khoa học: The tumor suppressor HIC1 (hypermethylated in cancer 1) is O-GlcNAc glycosylated

HIC1(hypermethylated in cancer 1) is a transcriptional repressor containing fiveKru¨ppel-likeC2H2zinc fingers and an N-terminal dimerization and autonomous repression domain called BTB/POZ. Here, we demonstrate that full-length HIC1 proteins are modified both in vivo andin vitro with O-linkedN-acetylglucosamine (O-GlcNAc). This is a highly dynamic glycosylation found within the cytosolic and the nuclear compartments of eukaryotes. Analysis of [ 3 H]Gal-labeled tryptic peptides indicates that HIC1 has three major sites forO-GlcNAc glycosylation | Eur. J. Biochem. 271 3843-3854 2004 FEBS 2004 doi The tumor suppressor HIC1 hypermethylated in cancer 1 is ỡ-GlcNAc glycosylated Tonv Lefebvre1 2. Sébastien Pinte1 Cateline Guerardel1. Sophie Deltour1 Nathalie Martin-Soudant1 Marie-Christine Slomianny2 Jean-Claude Michalski2 and Dominique Leprince1 1UMR 8526 du CNRS Institut de Biologie de Lille Institut Pasteur de Lille France 2UMR 8576 du CNRS Unite de Glycobiologie Structurale et Fonctionnelle Villeneuve d Ascq France HIC1 hypermethylated in cancer 1 is a transcriptional repressor containing five Kruppel-like C2H2 zinc fingers and an N-terminal dimerization and autonomous repression domain called BTB POZ. Here we demonstrate that fulllength HIC1 proteins are modified both in vivo and in vitro with O-linked N-acetylglucosamine O-GlcNAc . This is a highly dynamic glycosylation found within the cytosolic and the nuclear compartments of eukaryotes. Analysis of 3H Gal-labeled tryptic peptides indicates that HIC1 has three major sites for O-GlcNAc glycosylation. Using C-ter-minal deletion mutants we have shown that O-GlcNAc modification of HIC1 proteins occurred preferentially in the DNA-binding domain. Nonglycosylated and glycosylated forms of full-length HIC1 proteins separated by wheat germ agglutinin affinity purification displayed the same specific DNA-binding activity in electrophoretic mobility shift assays proving that the O-GlcNAc modification is not directly implicated in the specific DNA recognition of HIC1. Intriguingly N-terminal truncated forms corres ponding to BTB-POZ-deleted proteins exhibited a strikingly differential activity as the glycosylated truncated forms are unable to bind DNA whereas the unglycosylated ones do. Electrophoretic mobility shift assays performed with separated pools of glycosylated and unglycosylated forms of a construct exhibiting only the DNA-binding domain and the C-terminal tail of HIC1 residues 399-714 and supershift experiments with wheat .

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