School of Physical and Mathematical Sciences, Nanyang Technological University, Singapore 637371, Singapore.
NTU Institute of Structural Biology, Nanyang Technological University, Singapore 636921, Singapore.
Biochemistry. 2021 Apr 13;60(14):1097-1107. doi: 10.1021/acs.biochem.0c00916. Epub 2021 Mar 22.
Aberrant expansion of the hexanucleotide GGGGCC (or GC) repeat in the human gene is the most common genetic factor found behind amyotrophic lateral sclerosis and frontotemporal dementia. The hypothesized pathways, through which the repeat expansions contribute to the pathology, involve one or more secondary structural forms of the DNA and/or RNA sequences, such as G-quadruplexes, duplexes, and hairpins. Here, we study the structures of DNA and RNA duplexes formed by GC repeats, which contain G()·G() base pairs flanked by either G·C or C·G base pairs. We show that duplexes formed by GC repeats contain alternately two types of G·G pair contexts exhibiting different base flipping dynamics (∼100 ms vs ∼2 ms for DNA and ∼50 ms vs ∼20 ms for RNA at 10 °C, respectively) depending on the flanking bases, with the slow-flipping G·G pairs being flanked by a guanine at the 5'-end and the fast-flipping G·G pairs being flanked by a cytosine at the 5'-end. Our findings on the structures and dynamics of G·G base pairs in DNA and RNA duplexes formed by GC repeats provide a foundation for further studies of the functions and targeting of such biologically relevant motifs.
六核苷酸 GGGGCC（或 GC）重复序列在人类基因中的异常扩张是导致肌萎缩侧索硬化症和额颞叶痴呆的最常见遗传因素。据推测，这些重复序列通过一种或多种 DNA 和/或 RNA 序列的二级结构形式，如 G-四联体、双链体和发夹结构，导致了病理学的发生。在这里，我们研究了由 GC 重复序列形成的 DNA 和 RNA 双链体的结构，这些重复序列包含侧翼为 G·C 或 C·G 碱基对的 G()·G()碱基对。我们表明，由 GC 重复序列形成的双链体包含两种类型的交替 G·G 对结构，它们表现出不同的碱基翻转动力学（在 10°C 下，DNA 分别为∼100 ms 和∼2 ms，RNA 分别为∼50 ms 和∼20 ms），这取决于侧翼碱基，翻转速度较慢的 G·G 对被 5'-端的鸟嘌呤侧翼，翻转速度较快的 G·G 对被 5'-端的胞嘧啶侧翼。我们对 GC 重复序列形成的 DNA 和 RNA 双链体中 G·G 碱基对的结构和动力学的研究为进一步研究这些具有生物学相关性的基序的功能和靶向提供了基础。
