2. Academic Validation
  3. Discovery of A G-Quadruplex Unwinder That Unleashes the Translation of G-Quadruplex-Containing mRNA without Inducing DNA Damage

Discovery of A G-Quadruplex Unwinder That Unleashes the Translation of G-Quadruplex-Containing mRNA without Inducing DNA Damage

  • Angew Chem Int Ed Engl. 2024 Sep 16;63(38):e202407353. doi: 10.1002/anie.202407353.
Xucong Teng 1 2 3 4,  Difei Hu 1,  Yicong Dai 1,  Haitao Jing 5,  Wenxuan Hu 5,  Qiushuang Zhang 1,  Na Zhang 5,  Jinghong Li 1 2 3 4
Affiliations

Affiliations

  • 1 Department of Chemistry, Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology, Tsinghua University, Beijing, 100084, China.
  • 2 New Cornerstone Science Laboratory, Shenzhen, 518054, China.
  • 3 Beijing Life Science Academy, Beijing, 102209, China.
  • 4 Center for BioAnalytical Chemistry, Hefei National Laboratory of Physical Science at Microscale, University of Science and Technology of China, Hefei, 230026, China.
  • 5 High Magnetic Field Laboratory, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, 230031, China.
PMID: 38953247 DOI: 10.1002/anie.202407353
Abstract

To explore the mechanisms and therapeutic strategies for G-quadruplex (G4) mediated diseases, it is crucial to manipulate and intervene in intracellular G4 structures using small molecular tools. While hundreds of G4 stabilizers have been developed, there is a significant gap in the availability of G4 unwinding agents. Here, we propose a strategy to disrupt G-quadruplexes by forming G-C hydrogen bonds with chemically modified cytidine trimers. We validated a good G4 unwinder, the 2'-F cytidine trimer (2'-F C3). 2'-F C3 does not inhibit cell growth nor cause severe DNA damage at a concentration below 10 μM. Moreover, 2'-F C3 does not affect gene transcription nor RNA splicing, while it significantly enhances the translation of G4-containing mRNA and upregulates RNA splicing, RNA processing and cell cycle pathways. The discovery of this G4 unwinder provides a functional tool for the chemical modulation of G4s in living cells.

Keywords

DNA damage; G-quadruplex; chemical targeting; translation; unwinder.

Figures
Products