Human telomere, oncogenic promoter and 5'-UTR G-quadruplexes: diverse higher order DNA and RNA targets for cancer therapeutics.

Human telomere, oncogenic promoter and 5'-UTR G-quadruplexes: diverse higher order DNA and RNA targets for cancer therapeutics.
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人端粒,致癌启动子和5'-UTR G四链体:癌症治疗剂的高阶DNA和RNA靶标不同。

DOI:
10.1093/nar/gkm711
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发表时间:
2007
影响因子:
14.9
通讯作者:
Kuryavyi, Vitaly
Kuryavyi, Vitaly
中科院分区:
生物学2区
文献类型:
--
作者:
Patel, Dinshaw J.;Phan, Anh Tuan;Kuryavyi, Vitaly

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在一价阳离子溶液中,富含鸟嘌呤的DNA序列可以形成由堆积的G-G四联体稳定的G-四联体。单个G-链的长度和数量以及连接子残基的长度和序列上下文定义了G-四链所采用的不同拓扑。本文重点介绍了最近基于溶液核磁共振的G-四链结构,该结构由四个重复的人端粒在K+溶液中形成,以及富含鸟嘌呤的c-myc、c-kit和不同的bcl2癌基因启动子链,以及针对HIV-1整合酶的双分子G-四链。这样的结构测定有助于识别意想不到的支架,如互锁的G-四链体,以及以双链反转和V形环、三联体、混合四联体、腺嘌呤介导的五联体和六联体和快速回溯G-四联体对齐为代表的新拓扑结构。该综述还重点介绍了最近发现的位于RNA致癌序列5‘-非翻译区(5’-UTRs)翻译起始点附近的富鸟嘌呤序列。维持端粒长度的端粒酶活性可以通过端粒末端G-四链的形成来负向调节。该综述评估了与识别结合和稳定与端粒和致癌序列相关的不同G-四链支架的小分子药物的正在进行的努力的进展,并概述了根据配体-G-四链复合体的几种基于X射线的结构识别原理的进展。
Guanine-rich DNA sequences can form G-quadruplexes stabilized by stacked G–G–G–G tetrads in monovalent cation-containing solution. The length and number of individual G-tracts and the length and sequence context of linker residues define the diverse topologies adopted by G-quadruplexes. The review highlights recent solution NMR-based G-quadruplex structures formed by the four-repeat human telomere in K+ solution and the guanine-rich strands of c-myc, c-kit and variant bcl-2 oncogenic promoters, as well as a bimolecular G-quadruplex that targets HIV-1 integrase. Such structure determinations have helped to identify unanticipated scaffolds such as interlocked G-quadruplexes, as well as novel topologies represented by double-chain-reversal and V-shaped loops, triads, mixed tetrads, adenine-mediated pentads and hexads and snap-back G-tetrad alignments. The review also highlights the recent identification of guanine-rich sequences positioned adjacent to translation start sites in 5′-untranslated regions (5′-UTRs) of RNA oncogenic sequences. The activity of the enzyme telomerase, which maintains telomere length, can be negatively regulated through G-quadruplex formation at telomeric ends. The review evaluates progress related to ongoing efforts to identify small molecule drugs that bind and stabilize distinct G-quadruplex scaffolds associated with telomeric and oncogenic sequences, and outlines progress towards identifying recognition principles based on several X-ray-based structures of ligand–G-quadruplex complexes.
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