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Modification of the human thymine-DNA glycosylase by ubiquitin-like proteins facilitates enzymatic turnover

Hardeland, Ulrike and Steinacher, Roland and Jiricny, Josef and Schär, Primo. (2002) Modification of the human thymine-DNA glycosylase by ubiquitin-like proteins facilitates enzymatic turnover. The EMBO Journal, Vol. 21, H. 6. S. 1456-64.

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Official URL: http://edoc.unibas.ch/dok/A5839361

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Abstract

DNA glycosylases initiate base excision repair (BER) through the generation of potentially harmful abasic sites (AP sites) in DNA. Human thymine-DNA glycosylase (TDG) is a mismatch-specific uracil/thymine-DNA glycosylase with an implicated function in the restoration of G*C base pairs at sites of cytosine or 5-methylcytosine deamination. The rate-limiting step in the action of TDG in vitro is its dissociation from the product AP site, suggesting the existence of a specific enzyme release mechanism in vivo. We show here that TDG interacts with and is covalently modified by the ubiquitin-like proteins SUMO-1 and SUMO-2/3. SUMO conjugation dramatically reduces the DNA substrate and AP site binding affinity of TDG, and this is associated with a significant increase in enzymatic turnover in reactions with a G*U substrate and the loss of G*T processing activity. Sumoylation also potentiates the stimulatory effect of APE1 on TDG. These observations implicate a function of sumoylation in the controlled dissociation of TDG from the AP site and open up novel perspectives for the understanding of the molecular mechanisms coordinating the early steps of BER.
Faculties and Departments:03 Faculty of Medicine > Departement Biomedizin > Division of Biochemistry and Genetics > Molecular Genetics (Schär)
UniBasel Contributors:Schär, Primo Leo
Item Type:Article, refereed
Bibsysno:Link to catalogue
Publisher:Nature Publishing Group
ISSN:0261-4189
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:24 May 2013 09:10
Deposited On:26 Apr 2013 06:57

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