G-quadruplex conformation and dynamics are determined by loop length and sequence

Details

• Alternative Title:
  Nucleic Acids Res
• Personal Author:
  Tippana, Ramreddy ; Xiao, Weikun ; Myong, Sua
• Description:
  The quadruplex forming G-rich sequences are unevenly distributed throughout the human genome. Their enrichment in oncogenic promoters and telomeres has generated interest in targeting G-quadruplex (GQ) for an anticancer therapy. Here, we present a quantitative analysis on the conformations and dynamics of GQ forming sequences measured by single molecule fluorescence. Additionally, we relate these properties to GQ targeting ligands and G4 resolvase 1 (G4R1) protein binding. Our result shows that both the loop (non-G components) length and sequence contribute to the conformation of the GQ. Real time single molecule traces reveal that the folding dynamics also depend on the loop composition. We demonstrate that GQ-stabilizing small molecules, N-methyl mesoporphyrin IX (NMM), its analog, NMP and the G4R1 protein bind selectively to the parallel GQ conformation. Our findings point to the complexity of GQ folding governed by the loop length and sequence and how the GQ conformation determines the small molecule and protein binding propensity.
• Subjects:
  Base Sequence DEAD-box RNA Helicases DNA G-Quadruplexes Humans Kinetics Ligands Mesoporphyrins Structural Biology Telomere
• Source:
  Nucleic Acids Res. 2014; 42(12):8106-8114.
• Pubmed ID:
  24920827
• Pubmed Central ID:
  PMC4081081
• Document Type:
  Journal Article
• Funding:
  1DP2GM105453/DP/NCCDPHP CDC HHS/United States ; DP2 GM105453/GM/NIGMS NIH HHS/United States
• Volume:
  42
• Issue:
  12
• Collection(s):
  CDC Public Access
• Main Document Checksum:
  urn:sha256:c413ffc27048350dcba9efc92963a22e0354ca67afafa1f6375c5799d0a174c5
• Download URL:
  https://stacks.cdc.gov/view/cdc/32273/cdc_32273_DS1.pdf
• File Type:
  [PDF - 1.27 MB ]