Obata Shunsuke, Asamitsu Sefan, Hashiya Kaori, Bando Toshikazu, Sugiyama Hiroshi
Department of Chemistry, Graduate School of Science, Kyoto University , Kitashirakawa-Oiwakecho, Sakyo-ku, Kyoto 606-8502, Japan.
Institute for Integrated Cell-Material Sciences (WPI-iCeMS), Kyoto University , Yoshida-Ushinomiyacho, Sakyo-ku, Kyoto 606-8501, Japan.
Biochemistry. 2018 Feb 6;57(5):498-502. doi: 10.1021/acs.biochem.7b01059. Epub 2017 Dec 15.
The G-quadruplex (G4) is one type of higher-order structure of nucleic acids and is thought to play important roles in various biological events such as regulation of transcription and inhibition of DNA replication. Pyrrole-imidazole polyamides (PIPs) are programmable small molecules that can sequence-specifically bind with high affinity to the minor groove of double-stranded DNA (dsDNA). Herein, we designed head-to-head hairpin PIP dimers and their target dsDNA in a model G4-forming sequence. Using an electrophoresis mobility shift assay and transcription arrest assay, we found that PIP dimers could induce the structural change to G4 DNA from dsDNA through the recognition by one PIP dimer molecule of two duplex-binding sites flanking both ends of the G4-forming sequence. This induction ability was dependent on linker length. This is the first study to induce G4 formation using PIPs, which are known to be dsDNA binders. The results reported here suggest that selective G4 induction in native sequences may be achieved with PIP dimers by applying the same design strategy.
G-四链体（G4）是核酸的一种高级结构类型，被认为在诸如转录调控和DNA复制抑制等各种生物事件中发挥重要作用。吡咯-咪唑聚酰胺（PIP）是可编程的小分子，能够以序列特异性方式高亲和力结合双链DNA（dsDNA）的小沟。在此，我们在一个形成G4的模型序列中设计了头对头发夹状PIP二聚体及其靶标dsDNA。通过电泳迁移率变动分析和转录阻滞分析，我们发现PIP二聚体能够通过一个PIP二聚体分子识别形成G4序列两端侧翼的两个双链结合位点，诱导dsDNA向G4 DNA发生结构转变。这种诱导能力取决于连接子长度。这是首次使用已知为dsDNA结合剂的PIP诱导G4形成的研究。此处报道的结果表明，通过应用相同的设计策略，PIP二聚体可能在天然序列中实现选择性G4诱导。
