Cell cycle regulation as a mechanism for functional separation of the apparently redundant uracil DNA glycosylases TDG and UNG2
Open Access
- 25 May 2007
- journal article
- research article
- Published by Oxford University Press (OUP) in Nucleic Acids Research
- Vol. 35 (11) , 3859-3867
- https://doi.org/10.1093/nar/gkm337
Abstract
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.Keywords
This publication has 23 references indexed in Scilit:
- SUMO-1-Dependent Allosteric Regulation of Thymine DNA Glycosylase Alters Subnuclear Localization and CBP/p300 RecruitmentMolecular and Cellular Biology, 2007
- Proteolytic degradation of the nuclear isoform of uracil-DNA glycosylase occurs during the S phase of the cell cycleDNA Repair, 2004
- The versatile thymine DNA-glycosylase: a comparative characterization of the human, Drosophila and fission yeast orthologsNucleic Acids Research, 2003
- Uracil in DNA – occurrence, consequences and repairOncogene, 2002
- Cyclin A in cell cycle control and cancerCellular and Molecular Life Sciences, 2002
- Modification of the human thymine-DNA glycosylase by ubiquitin-like proteins facilitates enzymatic turnoverThe EMBO Journal, 2002
- Identification and functional characterization of the promoter region of the humanMSH6 geneGenes, Chromosomes and Cancer, 2001
- Thymine DNA glycosylaseProgress in Nucleic Acid Research and Molecular Biology, 2001
- Separating Substrate Recognition from Base Hydrolysis in Human Thymine DNA Glycosylase by Mutational AnalysisJournal of Biological Chemistry, 2000
- Dynamics of DNA Replication Factories in Living CellsThe Journal of cell biology, 2000