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

• Published in: Nucleic acids research Vol. 33; no. 19; pp. 6393 - 6404
• Main Authors: Lucey, Marie J., Chen, Dongsheng, Lopez-Garcia, Jorge, Hart, Stephen M., Phoenix, Fladia, Al-Jehani, Rajai, Alao, John P., White, Roger, Kindle, Karin B., Losson, Régine, Chambon, Pierre, Parker, Malcolm G., Schär, Primo, Heery, David M., Buluwela, Lakjaya, Ali, Simak
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 01-01-2005; Oxford Publishing Limited (England)
• Subjects: Amino Acid Motifs; Amino Acid Sequence; Animals; Biochemistry, Molecular Biology; Cercopithecus aethiops; Chlorocebus aethiops; COS Cells; Histone Acetyltransferases; Humans; Life Sciences; Molecular biology; Molecular Sequence Data; Nuclear Receptor Coactivator 1; Repetitive Sequences, Amino Acid; Thymine DNA Glycosylase; Thymine DNA Glycosylase - chemistry; Thymine DNA Glycosylase - metabolism; Trans-Activators; Trans-Activators - chemistry; Trans-Activators - metabolism; Transcription Factors; Transcription Factors - chemistry; Transcription Factors - metabolism; Tyrosine; Tyrosine - analysis
• ISSN: 0305-1048; 1362-4962; 1362-4962
• DOI: 10.1093/nar/gki940

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-α. 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.