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Originally published In Press as doi:10.1074/jbc.M104963200 on July 3, 2001

J. Biol. Chem., Vol. 276, Issue 36, 33569-33575, September 7, 2001
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The DNA Glycosylase T:G Mismatch-specific Thymine DNA Glycosylase Represses Thyroid Transcription Factor-1-activated Transcription*

Caterina MisseroDagger , Maria Teresa Pirro, Silvana Simeone, Michele Pischetola, and Roberto Di Lauro

From the Stazione Zoologica "A. Dohrn," Villa Comunale, 80121 Napoli, Italy

The transcription factor thyroid transcription factor-1 (TTF-1) is a homeodomain-containing protein that belongs to the NK2 family of genes involved in organogenesis. TTF-1 is required for normal development of the forebrain, lung, and thyroid. In a search for factors that regulate TTF-1 transcriptional activity, we isolated three genes (T:G mismatch-specific thymine DNA glycosylase (TDG), homeodomain-interacting protein kinase 2 (HIPK2), and Ajuba), whose products can interact with TTF-1 in yeast and in mammalian cells. TDG is an enzyme involved in base excision repair. In the present paper, we show that TDG acts as a strong repressor of TTF-1 transcriptional activity in a dose-dependent manner, while HIPK2 and Ajuba display no effect on TTF-1 activity, at least under the tested conditions. TDG-mediated inhibition occurs specifically on TTF-1-responsive promoters in thyroid and non thyroid cells. TDG associates with TTF-1 in mammalian cells through the TTF-1 carboxyl-terminal activation domain and is independent of the homeodomain. These findings reveal a previously unsuspected role for the repair enzyme TDG as a transcriptional repressor and open new routes toward the understanding of the regulation of TTF-1 transcriptional activity.

* This work was supported by grants from Associazione Italiana per la Ricerca sul Cancro, from the Consiglio Nazionale delle Ricerche "Target Project on Biotechnology" and "Post-transcriptional modification of gene expression," and from Ministero Universitá e Ricerca Scientifica e Tecnologica "Molecular mechanisms responsible for differentiation of thyroid cells: diagnostic and therapeutic applications" and the Programma Biotecnologie.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 GenBankTM/EMBL Data Bank with accession number(s) AY026945.

Dagger To whom correspondence should be addressed: TIGEM, Telethon Institute of Genetics and Medicine, Via P. Castellino 111, 80131 Napoli-Italy. Tel.: 39-081-6132219; Fax: 39-081-5609877; E-mail: missero@tigem.it.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.


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