Cell cycle regulation as a mechanism for functional separation of the apparently redundant uracil DNA glycosylases TDG and UNG2.
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.
Hardeland
Ulrike
U
Centre for Biomedicine, DKBW, University of Basel, Mattenstrasse 28, CH-4058 Basel, Switzerland.
Kunz
Christophe
C
Focke
Frauke
F
Szadkowski
Marta
M
Schär
Primo
P
D002453:Cell Cycle; D002460:Cell Line; D045647:DNA Glycosylases / Q000378:metabolism*; D004260:DNA Repair; D006801:Humans; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D016196:S Phase; D044502:Thymine DNA Glycosylase / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism; D051981:Uracil-DNA Glycosidase / Q000378:metabolism*
D025801:Ubiquitin; C492570:CCNO protein, human; D045647:DNA Glycosylases; D044502:Thymine DNA Glycosylase; D051981:Uracil-DNA Glycosidase; D046988:Proteasome Endopeptidase Complex