dna repair 6 ( 2 0 0 7 ) 489–504 available at www.sciencedirect.com journal homepage: www.elsevier.com/locate/dnarepair The enigmatic thymine DNA glycosylase Daniel Cort ´ azar, Christophe Kunz, Yusuke Saito, Roland Steinacher, Primo Sch ¨ ar ∗ Centre for Biomedicine, Department of Clinical Biological Research, University of Basel, Basel, Switzerland article info Article history: Published on line 20 November 2006 Keywords: BER TDG SUMO Deamination abstract When it was first isolated from extracts of HeLa cells in Josef Jiricny’s laboratory, the thymine DNA glycosylase (TDG) attracted attention because of its ability to remove thymine, i.e. a normal DNA base, from G·T mispairs. This implicated a function of DNA base excision repair in the restoration of G·C base pairs following the deamination of a 5-methylcytosine. TDG turned out to be the founding member of a newly emerging family of mismatch-directed uracil-DNA glycosylases, the MUG proteins, that act on a comparably broad spectrum of base lesion including G·U as the common, most efficiently processed substrate. However, because of its apparent catalytic inefficiency, some have considered TDG a poor DNA repair enzyme without an important biological function. Others have reported 5-meC DNA glyco- sylase activity to be associated with TDG, thrusting the enzyme into limelight as a possible DNA demethylase. Yet others have found the glycosylase to interact with transcription fac- tors, implicating a function in gene regulation, which appears to be critically important in developmental processes. This article reviews all these developments in view of possible biological functions of this multifaceted DNA glycosylase. © 2006 Elsevier B.V. All rights reserved. 1. Introduction Within cells, the chemically unstable DNA is under perma- nent hydrolytic and chemical attack. Hydrolytic reactions occur at a significant rate and include the deamination of DNA bases with exocylic amino groups, i.e. cytosine (C) and 5-methylcytosine (5-meC), adenine (A) and guanine (G) [1]. Deamination of C and 5-meC generates uracil (U) and thymine (T) mispaired with guanine, respectively, both giving rise to C·G to T·A transition, unless repaired. While U is a foreign base in DNA and is easily recognized and repaired as such, the cor- rection of a deaminated 5-meC, i.e. a T, requires a higher level of sophistication at damage recognition, since the “damage” in this case is a perfectly normal DNA base, except that it is mispaired. Such thoughts led Josef Jiricny and colleagues to search for a DNA repair function that processes T when mis- paired with G to restore a canonical G·C base pair. In transfec- ∗ Corresponding author. Tel.: +41 61 267 0767; fax: +41 61 367 3566. E-mail address: primo.schaer@unibas.ch (P. Sch¨ ar). tion experiments with G·T mismatched SV40 DNA they indeed identified a G·T directed repair activity in African green mon- key kidney cells that efficiently replaced the T with a C [2]. The subsequent purification of a G·T binding and processing enzyme from nuclear extracts of HeLa cells and the molecular cloning of the respective cDNA eventually led to the discov- ery of the human thymine DNA glycosylase (TDG) [3–5], the first mismatch-specific DNA glycosylase to be described. Its ability to hydrolyze thymine and uracil from G·T and G·U mis- pairs in vitro [6] implicated a specific biological role in base excision repair (BER) of deaminated 5-meC and C, i.e. in coun- tering deamination-induced C → T mutation. During the last decade, research on TDG has seen an impressive expansion into different disciplines. Enzymatic and structural studies provided insight into different aspects of its functionality. The identification and characterization of homologs and orthologs of species across the phylogeny shed 1568-7864/$ – see front matter © 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.dnarep.2006.10.013