EFFECTS OF ANTIMETABOLITES ON RNA METABOLISM

许多抗代谢物（如核苷类似物）已被证明， 具有化疗效果。 在这些药物中，5-氟尿嘧啶（FUra） 是一种广泛使用的药物，其作用机制尚不清楚。 许多实验室已经证明了将FUra掺入RNA中， 这被认为是其三大行动场所之一。 另 两个主要作用是1）转化为脱氧核糖核苷酸， 抑制胸苷酸合成酶和2）转化为 脱氧核糖核苷三磷酸和可能掺入DNA。 这 这项研究将集中于FUra掺入RNA后的作用。 以前，主要的RNA效应被认为是抑制 核糖体RNA（rRNA）成熟。 我们的实验室先前证明 信使RNA（mRNA）的错误编码似乎发生在 对rRNA没有明显影响的FUra。 这项研究是基于初步观察，即FURA导致 二氢叶酸还原酶（DHFR）和几种 RNA的种类 具体而言，我们建议研究以下问题。 1)进一步评估FUra掺入RNA对酶的影响 从取代的mRNA合成（使用DHFR和DHFR mRNA作为模型 酶和mRNA）。 2)FURA对RNA加工的影响（特别是DHFR RNA作为模型） 无论是在体内还是体外。 3)FUra对小核RNA的影响（使用U1 RNA作为模型）。 4)rRNA。 将评估这四个可能地点的相对重要性。 的 本研究的结果将能够提供手段和模型，以研究 掺入的其他核苷类似物的RNA介导效应 转化成RNA

A number of antimetabolites (e.g. nucleoside analogs) have been shown to have a chemotherapeutic effect. Among these agents, 5-fluorouracil (FUra) is a widely used agent whose mechanism of action is still not clear. Numerous laboratories have demonstrated incorporation of FUra into RNA and this is considered to be one of its three major sites of action. The other two major effects are 1) conversion to the deoxyribonucleotide and inhibition of thymidylate synthetase and 2) conversion to the deoxyribonucleoside triphosphate and possible incorporation into DNA. This study will concentrate on the effects of FUra due to incorporation into RNA. Previously, the major RNA effect was considered to be inhibition of ribosomal RNA (rRNA) maturation. Our laboratory previously demonstrated that miscoding of messenger RNA (mRNA) appears to occur at concentrations of FUra where no effect on rRNA is evident. The study is based upon the preliminary observation that FUra causes an alteration in the properties of dihydrofolate reductase (DHFR) and several species of RNA. Specifically, we propose to study the following. 1) Further evaluate the effects of FUra incorporation into RNA on enzymes synthesized from the substituted mRNA (using DHFR and DHFR mRNA as a model enzyme and mRNA, respectively). 2) The effect of FUra on RNA processing (specifically DHFR RNA as a model) both in vivo and in vitro. 3) The effect of FUra on small nuclear RNA (using U1 RNA as a model). 4) rRNA. The relative importance of these four possible sites will be assessed. The results of this study will be able to provide means and models to study the RNA-mediated effects of other nucleoside analogs which are incorporated into RNA.