Molecular mechanisms for maintenance of G-rich short tandem repeats capable of adopting G4 DNA structures
Molecular mechanisms for maintenance of G-rich short tandem repeats capable of adopting G4 DNA structures
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DOI：
10.1016/j.mrfmmm.2006.01.014
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发表时间：
2006-06-25
影响因子：
2.3
通讯作者：
Fukuda, Hirokazu
中科院分区：
文献类型：
--
作者：
Nakagama, Hitoshi;Higuchi, Kumiko;Fukuda, Hirokazu
哺乳动物基因组包含几种类型的重复序列。其中一些序列涉及各种特定的细胞事件，包括减数分裂重组、染色体断裂和转录调节，以及多种人类疾病。在这篇综述中，我们记录了在几个小卫星、端粒和各种三重重复序列中发现的富含G的重复序列对DNA二级结构的形成，并报告了它们对体外DNA合成的影响。通过NMR和CD谱分析，证明小鼠小卫星Pc-1中的d（GGCAG）重复序列形成了分子内折叠的四链体结构（又称G4'结构）。d（TTAGGG）端粒重复序列和d（CGG）三联体重复序列也分别形成G4'和其他未指明的高级结构。在体外DNA合成基本上被逮捕的重复，这可能是负责的优先突变的G-丰富的重复序列。使用NIH 3 T3细胞提取物的电泳迁移率变动分析揭示了异质性核核糖核蛋白（hnRNP）A1和A3，其紧密且特异性地与d（GGCAG）和d（TTAGGG）重复序列结合，K-d值在nM的数量级。HnRNP A1使d（GGCAG）和d（TTAGGG）重复区域中形成的G4'结构展开，并且还解析了由d（CGG）三联重复形成的高级结构。此外，DNA合成阻滞在二级结构的d（GGCAG）重复，端粒和d（CGG）三联体重复被有效地抑制通过添加hnRNP A1。hnRNP的高表达可能有助于维持富含G的重复序列，包括端粒重复序列，并且还可能参与确保具有增强的增殖的细胞中基因组的稳定性。基因的转录调控，如c-myc和胰岛素，G4序列中发现的启动子区域可能是一个有趣的研究领域，并有助于进一步阐明hnRNP家族蛋白在人类疾病中的生物学功能。(c)2006 Elsevier B. V.保留所有权利。
Mammalian genomes contain several types of repetitive sequences. Some of these sequences are implicated in various specific cellular events, including meiotic recombination, chromosomal breaks and transcriptional regulation, and also in several human disorders. In this review, we document the formation of DNA secondary structures by the G-rich repetitive sequences that have been found in several minisatellites, telomeres and in various triplet repeats, and report their effects on in vitro DNA synthesis. d(GGCAG) repeats in the mouse minisatellite Pc-1 were demonstrated to form an intra-molecular folded-back quadruplex structure (also called a G4' structure) by NMR and CD spectrum analyses. d(TTAGGG) telomere repeats and d(CGG) triplet repeats were also shown to form G4' and other unspecified higher order structures, respectively. In vitro DNA synthesis was substantially arrested within the repeats, and this could be responsible for the preferential mutability of the G-rich repetitive sequences. Electrophoretic mobility shift assays using NIH3T3 cell extracts revealed heterogeneous nuclear ribonucleoprotein (hnRNP) A1 and A3, which were tightly and specifically bound to d(GGCAG) and d(TTAGGG) repeats with K-d values in the order of nM. HnRNP A1 unfolded the G4' structure formed in the d(GGCAG), and d(TTAGGG), repeat regions, and also resolved the higher order structure formed by d(CGG) triplet repeats. Furthermore, DNA synthesis arrest at the secondary structures of d(GGCAG) repeats, telomeres and d(CGG) triplet repeats was efficiently repressed by the addition of hnRNP A1. High expression of hnRNPs may contribute to the maintenance of G-rich repetitive sequences, including telomere repeats, and may also participate in ensuring the stability of the genome in cells with enhanced proliferation. Transcriptional regulation of genes, such as c-myc and insulin, by G4 sequences found in the promoter regions could be an intriguing field of research and help further elucidate the biological functions of the hnRNP family of proteins in human diseases. (c) 2006 Elsevier B.V. All rights reserved.