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Nucleic Acids Research 2005 33(19):6393-6404; doi:10.1093/nar/gki940
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Published online 10 November 2005

© The Author 2005. Published by Oxford University Press. All rights reserved
The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that: the original authorship is properly and fully attributed; the Journal and Oxford University Press are attributed as the original place of publication with the correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact journals.permissions{at}oxfordjournals.org

Article

T:G mismatch-specific thymine-DNA glycosylase (TDG) as a coregulator of transcription interacts with SRC1 family members through a novel tyrosine repeat motif

Marie J. Lucey, Dongsheng Chen, Jorge Lopez-Garcia, Stephen M. Hart, Fladia Phoenix, Rajai Al-Jehani, John P. Alao, Roger White1, Karin B. Kindle2, Régine Losson3, Pierre Chambon3, Malcolm G. Parker1, Primo Schär4, David M. Heery2, Lakjaya Buluwela and Simak Ali*

Department of Oncology, Imperial College London Du Cane Road, London W12 0NN, UK 1Institute of Reproductive and Developmental Biology, Imperial College London Du Cane Road, London W12 0NN, UK 2School of Pharmacy, University of Nottingham, University Park Nottingham NG7 2RD, UK 3Institut de Génétique et de Biologie Moléculaire et Cellulaire BP10142, 67404 Illkirch-Cedex, France 4Institute of Molecular Cancer Research, University of Zurich August Forel Strasse 7, CH-8008 Zurich, Switzerland

*To whom correspondence should be addressed. Tel: +44 20 8383 3789; Fax: +44 20 8383 5830; Email: simak.ali{at}imperial.ac.uk

Received August 30, 2005. Revised October 17, 2005. Accepted October 17, 2005.

Gene activation involves protein complexes with diverse enzymatic activities, some of which are involved in chromatin modification. We have shown previously that the base excision repair enzyme thymine DNA glycosylase (TDG) acts as a potent coactivator for estrogen receptor-{alpha}. To further understand how TDG acts in this context, we studied its interaction with known coactivators of nuclear receptors. We find that TDG interacts in vitro and in vivo with the p160 coactivator SRC1, with the interaction being mediated by a previously undescribed motif encoding four equally spaced tyrosine residues in TDG, each tyrosine being separated by three amino acids. This is found to interact with two motifs in SRC1 also containing tyrosine residues separated by three amino acids. Site-directed mutagenesis shows that the tyrosines encoded in these motifs are critical for the interaction. The related p160 protein TIF2 does not interact with TDG and has the altered sequence, F-X-X-X-Y, at the equivalent positions relative to SRC1. Substitution of the phenylalanines to tyrosines is sufficient to bring about interaction of TIF2 with TDG. These findings highlight a new protein–protein interaction motif based on Y-X-X-X-Y and provide new insight into the interaction of diverse proteins in coactivator complexes.

Simak Ali and Lakjaya Buluwela would like to dedicate this work to the memory of their colleague and friend Dr David Vigushin


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