Long-range DNA interactions: inter-molecular G-quadruplexes and their potential biological relevance.
Long-range DNA interactions: inter-molecular G-quadruplexes and their potential biological relevance.
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DOI：
10.1039/d2cc04872h
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发表时间：
2022-11-17
影响因子：
4.9
通讯作者：
Di Antonio, Marco
中科院分区：
文献类型：
--
作者：
Liano, Denise;Monti, Ludovica;Chowdhury, Souroprobho;Raguseo, Federica;Di Antonio, Marco
已知富含鸟嘌呤的DNA序列可以折叠成称为g -四联体（G4s）的二级结构，它可以由单个DNA链（分子内）或多个DNA链（分子间，iG4s）形成。分子内G4s由于在基因启动子和端粒中富集而成为广泛生物学研究的对象。另一方面，iG4s从未在生物学背景下被考虑过，因为DNA远端序列之间的相互作用在细胞中形成iG4一直被认为是极不可能的。在这篇专题文章中，我们通过展示我们最近发现的第一个对iG4s具有惊人的皮摩尔亲和力和结合选择性的人类蛋白（CSB）来挑战这一教条。这些发现表明iG4结构可能在细胞中形成，并强调需要进一步研究以揭示这些分子间DNA结构的基本生物学作用。此外，我们讨论了由C9orf72基因的重复扩增触发的神经元细胞中iG4s形成的潜力如何导致ALS和FTD等神经退行性疾病中基于核酸的病理聚集体的形成。最后，基于我们最近在短rna修饰探针上的工作，我们对如何利用g4选择性化学工具的合理设计来进一步阐明iG4结构在衰老相关疾病中的生物学相关性提供了展望。分子间g -四重结构可以在基因组DNA的远端区域形成，有助于染色质环。在此，我们讨论了支持iG4s在活细胞中形成及其潜在生物学功能的最新证据。
Guanine-rich DNA sequences are known to fold into secondary structures called G-quadruplexes (G4s), which can form from either individual DNA strands (intra-molecular) or multiple DNA strands (inter-molecular, iG4s). Intra-molecular G4s have been the object of extensive biological investigation due to their enrichment in gene-promoters and telomers. On the other hand, iG4s have never been considered in biological contexts, as the interaction between distal sequences of DNA to form an iG4 in cells was always deemed as highly unlikely. In this feature article, we challenge this dogma by presenting our recent discovery of the first human protein (CSB) displaying astonishing picomolar affinity and binding selectivity for iG4s. These findings suggest potential for iG4 structures to form in cells and highlight the need of further studies to unravel the fundamental biological roles of these inter-molecular DNA structures. Furthermore, we discuss how the potential for formation of iG4s in neuronal cells, triggered by repeat expansions in the C9orf72 gene, can lead to the formation of nucleic-acids based pathological aggregates in neurodegenerative diseases like ALS and FTD. Finally, based on our recent work on short LNA-modified probes, we provide a prespective on how the rational design of G4-selective chemical tools can be leveraged to further elucidate the biological relevance of iG4 structures in the context of ageing-related diseases. Intermolecular G-quadruplex structures can form within distal region of genomic DNA, contributing to chromatin looping. Herein, we discuss recent evidence supporting formation of iG4s in living cells and their potential biological function.
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