Hu Chun-Mei, Chang Zee-Fen
Graduate Institute of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, No. 1, Section 1, Jen-Ai Road, Taipei, 100, Taiwan.
J Biomed Sci. 2007 Jul;14(4):491-7. doi: 10.1007/s11373-007-9175-1. Epub 2007 May 25.
The fidelity of DNA replication in eukaryotic cells requires a balanced dNTP supply in the S phase. During the cell cycle progression, the production of dTTP is highly regulated to coordinate with DNA replication. Intracellular thymidine is salvaged to dTTP by cytosolic thymidine kinase (TK1) and thymidylate kinase (TMPK), both of which expression increase in the G1/S transition and diminish in the mitotic phase via proteolytic destruction. Anaphase promoting complex/cyclosome (APC/C)-mediated ubiquitination targets TK1 and TMPK to undergo proteasomal degradation in mitosis, by which dTTP pool is minimized in the early G1 phase of the next cell cycle. In this review, we will focus on regulation of TK1 in the post-S phase and the importance of mitotic proteolysis in controlling dNTP balance, replication stress and genomic stability. Finally, we discuss how thymidine pool and oligomeric forms of TK1 can affect mitotic control of dTTP.
真核细胞中DNA复制的保真度需要在S期有平衡的脱氧核苷酸三磷酸（dNTP）供应。在细胞周期进程中，胸苷三磷酸（dTTP）的产生受到高度调控，以与DNA复制相协调。胞内胸苷通过胞质胸苷激酶（TK1）和胸苷酸激酶（TMPK） salvage为dTTP，二者的表达在G1/S期转换时增加，并在有丝分裂期通过蛋白水解破坏而减少。后期促进复合体/细胞周期体（APC/C）介导的泛素化作用使TK1和TMPK在有丝分裂过程中被蛋白酶体降解，由此在下一个细胞周期的G1早期dTTP库最小化。在本综述中，我们将聚焦于S期后TK1的调控以及有丝分裂蛋白水解在控制dNTP平衡、复制应激和基因组稳定性方面的重要性。最后，我们讨论胸苷库和TK1的寡聚形式如何影响dTTP的有丝分裂控制。
