Hardeland Ulrike, Kunz Christophe, Focke Frauke, Szadkowski Marta, Schär Primo
Centre for Biomedicine, DKBW, University of Basel, Mattenstrasse 28, CH-4058 Basel, Switzerland.
Nucleic Acids Res. 2007;35(11):3859-67. doi: 10.1093/nar/gkm337. Epub 2007 May 25.
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.
人类胸腺嘧啶-DNA糖基化酶（TDG）是尿嘧啶DNA糖基化酶（UDG）超家族的成员。当双链DNA中的胸腺嘧啶与鸟嘌呤错配时，它能切除尿嘧啶、胸腺嘧啶以及一些化学碱基损伤。这些活性并非TDG所特有；哺乳动物细胞中至少还存在另外三种具有类似酶活性的蛋白质。这些酶的成功共同进化意味着存在必须协调的非冗余生物学功能。在此，我们报告细胞周期调控是一种使看似冗余的DNA糖基化酶实现功能分离的机制。我们发现进入S期的细胞通过泛素-蛋白酶体系统清除TDG，然后在G2期之前维持无TDG状态。异位表达的TDG不完全降解会阻碍S期进程和细胞增殖。TDG的细胞周期调控模式与UNG2的模式严格相反，UNG2在整个S期达到峰值，然后下降到检测不到的水平，直到在下一个S期之前再次出现。因此，TDG和UNG2依赖的碱基切除修复在整个细胞周期中交替进行，泛素-蛋白酶体途径构成了潜在的调控系统。
