SUMO-1-dependent allosteric regulation of thymine DNA glycosylase alters subnuclear localization and CBP/p300 recruitment.
Previous studies have demonstrated that the base excision repair enzyme thymine DNA glycosylase (TDG) mediates recruitment of histone acetyltransferases CREB-binding protein (CBP) and p300 to DNA, suggesting a plausible role for these factors in TDG-mediated repair. Furthermore, TDG was found to potentiate CBP/p300-dependent transcription and serve as a substrate for ... CBP/p300 acetylation. Here, we show that the small ubiquitin-like modifier 1 (SUMO-1) protein binding activity of TDG is essential for activation of CBP and localization to promyelocytic leukemia protein oncogenic domains (PODs). SUMO-1 binding is mediated by two distinct amino- and carboxy-terminal motifs (residues 144 to 148 and 319 to 322) that are negatively regulated by DNA binding via an amino-terminal hydrophilic region (residues 1 to 121). TDG is also posttranslationally modified by covalent conjugation of SUMO-1 (sumoylation) to lysine 341. Interestingly, we found that sumoylation of TDG blocks interaction with CBP and prevents TDG acetylation in vitro. Furthermore, sumoylation effectively abrogates intermolecular SUMO-1 binding and a sumoylation-deficient mutant accumulates in PODs, suggesting that sumoylation negatively regulates translocation to these nuclear structures. These findings suggest that TDG sumoylation promotes intramolecular interactions with amino- and carboxy-terminal SUMO-1 binding motifs that dramatically alter the biochemical properties and subcellular localization of TDG.
Mesh Terms:
Allosteric Site, Amino Acid Motifs, Amino Acid Sequence, Animals, Cell Line, Tumor, DNA Repair, Gene Expression Regulation, Enzymologic, Humans, Mice, Molecular Sequence Data, Protein Structure, Tertiary, SUMO-1 Protein, Sequence Homology, Amino Acid, Small Ubiquitin-Related Modifier Proteins, Thymine DNA Glycosylase, Transcription, Genetic, p300-CBP Transcription Factors
Allosteric Site, Amino Acid Motifs, Amino Acid Sequence, Animals, Cell Line, Tumor, DNA Repair, Gene Expression Regulation, Enzymologic, Humans, Mice, Molecular Sequence Data, Protein Structure, Tertiary, SUMO-1 Protein, Sequence Homology, Amino Acid, Small Ubiquitin-Related Modifier Proteins, Thymine DNA Glycosylase, Transcription, Genetic, p300-CBP Transcription Factors
Mol. Cell. Biol.
Date: Jan. 01, 2007
PubMed ID: 17060459
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