Chu E, Allegra C J
NCI-Navy Medical Oncology Branch, National Cancer Institute, Bethesda, MD 20889-5105, USA.
Adv Enzyme Regul. 1996;36:143-63. doi: 10.1016/0065-2571(95)00004-6.
Thymidylate synthase plays a central role in the biosynthesis of thymidylate, an essential precursor for DNA biosynthesis. In addition to its role in catalysis and cellular metabolism, studies from our laboratory have shown that thymidylate synthase functions as an RNA binding protein. Specifically, thymidylate synthase binds with high affinity to its own mRNA resulting in translational repression. An extensive series of experiments have now been performed to elucidate the molecular elements underlying the interaction between thymidylate synthase and its own mRNA. These studies have shed new light into the critical nucleotide sequences and/or secondary structure that are important for protein recognition. As well, studies to define the domains on the protein essential for RNA binding are currently underway. In addition to the characterization of the cis- and trans-acting elements underlying the interaction between thymidylate synthase and its own mRNA, we have recently shown that thymidylate synthase has the capacity to specifically bind in vitro and in vivo to other cellular RNA species. In this regard, thymidylate synthase interacts with the mRNAs of the c-myc onocogene and the p53 tumor suppressor gene. These two genes have been shown to play critical roles in cell cycle control, DNA biosynthesis, and apoptosis. In vitro studies reveal that the interaction of TS with these cell-cycle related mRNAs results in their translational repression. While the biological significance of these cellular RNA/TS protein interactions remains to be defined, these studies suggest a potential role for TS as a mediator in the coordinate regulation of several critical aspects of cellular metabolism.
胸苷酸合成酶在胸苷酸的生物合成中起着核心作用，胸苷酸是DNA生物合成必不可少的前体。除了其在催化和细胞代谢中的作用外，我们实验室的研究表明，胸苷酸合成酶还作为一种RNA结合蛋白发挥作用。具体而言，胸苷酸合成酶以高亲和力与其自身的mRNA结合，导致翻译抑制。现在已经进行了一系列广泛的实验，以阐明胸苷酸合成酶与其自身mRNA相互作用的分子基础。这些研究为对蛋白质识别重要的关键核苷酸序列和/或二级结构提供了新的线索。同样，目前正在进行确定蛋白质上对RNA结合至关重要的结构域的研究。除了表征胸苷酸合成酶与其自身mRNA相互作用的顺式和反式作用元件外，我们最近还表明，胸苷酸合成酶在体外和体内都有能力特异性结合其他细胞RNA种类。在这方面，胸苷酸合成酶与原癌基因c-myc和抑癌基因p53的mRNA相互作用。这两个基因已被证明在细胞周期控制、DNA生物合成和细胞凋亡中起关键作用。体外研究表明，TS与这些细胞周期相关mRNA的相互作用导致它们的翻译抑制。虽然这些细胞RNA/TS蛋白相互作用的生物学意义尚待确定，但这些研究表明TS在细胞代谢几个关键方面的协调调节中可能作为一种介质发挥作用。
