Koralewska Natalia, Szczepanska Agnieszka, Ciechanowska Kinga, Wojnicka Marta, Pokornowska Maria, Milewski Marek C, Gudanis Dorota, Baranowski Daniel, Nithin Chandran, Bujnicki Janusz M, Gdaniec Zofia, Figlerowicz Marek, Kurzynska-Kokorniak Anna
Department of Molecular and Systems Biology, Institute of Bioorganic Chemistry Polish Academy of Sciences, 61-704, Poznan, Poland.
Department of Ribonucleoprotein Biochemistry, Institute of Bioorganic Chemistry Polish Academy of Sciences, Noskowskiego 12/14, 61-704, Poznan, Poland.
Cell Mol Life Sci. 2021 Apr;78(7):3709-3724. doi: 10.1007/s00018-021-03795-w. Epub 2021 Mar 17.
Guanine (G)-rich single-stranded nucleic acids can adopt G-quadruplex structures. Accumulating evidence indicates that G-quadruplexes serve important regulatory roles in fundamental biological processes such as DNA replication, transcription, and translation, while aberrant G-quadruplex formation is linked to genome instability and cancer. Understanding the biological functions played by G-quadruplexes requires detailed knowledge of their protein interactome. Here, we report that both RNA and DNA G-quadruplexes are bound by human Dicer in vitro. Using in vitro binding assays, mutation studies, and computational modeling we demonstrate that G-quadruplexes can interact with the Platform-PAZ-Connector helix cassette of Dicer, the region responsible for anchoring microRNA precursors (pre-miRNAs). Consequently, we show that G-quadruplexes efficiently and stably inhibit the cleavage of pre-miRNA by Dicer. Our data highlight the potential of human Dicer for binding of G-quadruplexes and allow us to propose a G-quadruplex-driven sequestration mechanism of Dicer regulation.
富含鸟嘌呤（G）的单链核酸可以形成G-四链体结构。越来越多的证据表明，G-四链体在DNA复制、转录和翻译等基本生物学过程中发挥着重要的调节作用，而异常的G-四链体形成与基因组不稳定和癌症有关。了解G-四链体的生物学功能需要详细了解其蛋白质相互作用组。在这里，我们报告RNA和DNA G-四链体在体外均与人Dicer结合。通过体外结合试验、突变研究和计算建模，我们证明G-四链体可以与Dicer的平台-PAZ-连接螺旋盒相互作用，该区域负责锚定微小RNA前体（pre-miRNA）。因此，我们表明G-四链体有效且稳定地抑制Dicer对pre-miRNA的切割。我们的数据突出了人Dicer结合G-四链体的潜力，并使我们能够提出一种由G-四链体驱动的Dicer调节的隔离机制。
