Suppression of Gene Expression by G-Quadruplexes in Open Reading Frames Depends on G-Quadruplex Stability
Suppression of Gene Expression by G-Quadruplexes in Open Reading Frames Depends on G-Quadruplex Stability
复制标题
DOI：
10.1002/anie.201300058
复制
发表时间：
2013-01-01
影响因子：
16.6
通讯作者：
Sugimoto, Naoki
中科院分区：
文献类型：
--
作者：
Endoh, Tamaki;Kawasaki, Yu;Sugimoto, Naoki
富含鸟嘌呤（富含 G）的 DNA 序列形成 G-四联体，这是一种由堆叠的 G-四联体稳定的非规范结构，G-四联体由四个鸟嘌呤碱基组成，通过 Hoogsteen 型氢键相互作用。 [1] G-四链体因其独特的结构和在生理条件下的稳定性而被从物理、化学和生物学的角度进行了研究。[2, 3] 最具有特征的 G-四链体是由染色体末端富含 G 的 DNA 重复序列（称为端粒）形成的。[1]由于端粒在染色体维持和保护中发挥重要功能，因此端粒区域 G-四链体形成的潜力对于治疗具有潜在的重要性。富含G的RNA也可以形成G四链体；这些结构比同等 DNA 序列形成的结构具有更高的熔解温度。[4-6] RNA G 四链体的高热力学稳定性可能会影响各种生物过程，如复制、转录和转录后编辑。[7-12] 生物信息学研究表明，在癌基因 mRNA 的 5’非翻译区 (UTR) 中发现了具有四链体形成潜力 (SQFP) 的序列。 [13]由于这些 mRNA 的蛋白质表达在添加 G-四链体配体时会减少，而在掺入破坏 G-四链体形成的突变时会增加，[14-17] 据推测，5'UTR 中的四链体形成序列通过形成 RNA G-四链体来调节蛋白质表达水平。与 5'UTR 中的 RNA G-四链体对基因表达的影响相反，有关 G-四链体的信息很少。在 mRNA 的开放阅读框 (ORF) 中。翻译过程中 ORF 和 5'UTR 区域之间的一个已知差异是，由小核糖体亚基和大核糖体亚基组成的成熟核糖体沿着 ORF 前进，而只有与起始 tRNA 复合的小核糖体亚基在翻译开始前扫描 5'UTR。有人认为，处于延伸阶段的成熟核糖体比小核糖体亚基更能有效地解开 mRNA 中的下游双链体
Guanine-rich (G-rich) sequences of DNA form G-quadruplexes, a non-canonical structure stabilized by stacked G-quartets consisting of four guanine bases that interact through Hoogsteen-type hydrogen bonds.[1] G-quadruplexes have been studied from physical, chemical, and biological points of view because of their unique structure and stability under physiological conditions.[2, 3] The best characterized G-quadruplex is that formed by the G-rich repeats of DNA at the ends of chromosomes, termed telomeres.[1] Because the telomere performs essential functions in chromosome maintenance and protection, the potential for G-quadruplex formation in telomere regions has potential importance for therapies. G-rich RNA can also form G-quadruplexes; these structures have higher melting temperatures than those formed by equivalent DNA sequences.[4–6] The high thermodynamic stability of RNA G-quadruplexes may affect various biological processes such as replication, transcription, and post-transcriptional editing.[7–12] Bioinformatic studies have revealed that sequences with quadruplex-forming potential (SQFPs) are found in the 5’untranslated regions (UTRs) of oncogene mRNAs.[13] Because protein expression from these mRNAs decreases upon addition of G-quadruplex ligands and increases when mutations that disrupt the G-quadruplex formation are incorporated,[14–17] it is assumed that the quadruplex-forming sequences in the 5’UTRs regulate protein-expression levels through formation of RNA G-quadruplexes.In contrast to the effects of RNA G-quadruplexes in 5’UTRs on gene expression, there is little information about G-quadruplexes in the open reading frames (ORFs) of mRNAs. One known difference between ORF and 5’UTR regions during translation is that mature ribosomes, consisting of both small and large ribosomal subunits, progress along ORFs, whereas only the small ribosomal subunit complexed with the initiator tRNA scans the 5’UTR before initiation of translation. It has been suggested that the mature ribosome in the elongation phase can unwind downstream duplexes in mRNAs more effectively than the small ribosomal subunit