Nucleic Acids Research Advance Access originally published online on May 25, 2007
Nucleic Acids Research 2007 35(11):3859-3867; doi:10.1093/nar/gkm337
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Nucleic Acids Research, 2007, Vol. 35, No. 11 3859-3867
© 2007 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Nucleic Acid Enzymes |
Cell cycle regulation as a mechanism for functional separation of the apparently redundant uracil DNA glycosylases TDG and UNG2
1Centre for Biomedicine, DKBW, University of Basel, Mattenstrasse 28, CH-4058 Basel, Switzerland, 2Molecular Metabolic Control, DKFZ, Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany and 3KuDOS Pharmaceuticals Ltd., 327 Cambridge Science Park, Milton Road, Cambridge, CB4 0WG, UK
*To whom correspondence should be addressed. Tel: +41 0 61 267 0767; Fax: +41 0 61 267 3566; Email: primo.schaer{at}unibas.ch
Received March 5, 2007. Revised April 18, 2007. Accepted April 19, 2007.
Human Thymine-DNA Glycosylase (TDG) is a member of the uracil DNA glycosylase (UDG) superfamily. It excises uracil, thymine and a number of chemical base lesions when mispaired with guanine in double-stranded DNA. These activities are not unique to TDG; at least three additional proteins with similar enzymatic properties are present in mammalian cells. The successful co-evolution of these enzymes implies the existence of non-redundant biological functions that must be coordinated. Here, we report cell cycle regulation as a mechanism for the functional separation of apparently redundant DNA glycosylases. We show that cells entering S-phase eliminate TDG through the ubiquitin–proteasome system and then maintain a TDG-free condition until G2. Incomplete degradation of ectopically expressed TDG impedes S-phase progression and cell proliferation. The mode of cell cycle regulation of TDG is strictly inverse to that of UNG2, which peaks in and throughout S-phase and then declines to undetectable levels until it appears again just before the next S-phase. Thus, TDG- and UNG2-dependent base excision repair alternates throughout the cell cycle, and the ubiquitin–proteasome pathway constitutes the underlying regulatory system.
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.