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Molecular and Cellular Biology, January 2007, p. 229-243, Vol. 27, No. 1
0270-7306/07/$08.00+0     doi:10.1128/MCB.00323-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

SUMO-1-Dependent Allosteric Regulation of Thymine DNA Glycosylase Alters Subnuclear Localization and CBP/p300 Recruitment{triangledown} ,{dagger}

Ryan D. Mohan,1,{ddagger} Anita Rao,1,{ddagger} Jason Gagliardi,2,{ddagger} and Marc Tini1,2*

Departments of Physiology and Pharmacology,1 Department of Microbiology and Immunology, Siebens-Drake Medical Research Institute, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada N6G 2V42

Received 21 February 2006/ Returned for modification 26 April 2006/ Accepted 10 October 2006

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.

* Corresponding author. Mailing address: Department of Physiology and Pharmacology, Siebens-Drake Medical Research Institute, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada N6G 2V4. Phone: (519) 850-2942. Fax: (519) 661-3827. E-mail: mtini{at}uwo.ca.

{triangledown} Published ahead of print on 23 October 2006.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

{ddagger} R.D.M., A.R., and J.G. contributed equally to the manuscript.

Molecular and Cellular Biology, January 2007, p. 229-243, Vol. 27, No. 1
0270-7306/07/$08.00+0     doi:10.1128/MCB.00323-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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