Structural Dynamics Role of AGG Interruptions in Inhibition CGG Repeat Expansion Associated with Fragile X Syndrome

Yang I. Shen, Kai Chun Cheng, Yu Jie Wei, I. Ren Lee*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Abnormal expansion of trinucleotide CGG repeats is responsible for Fragile X syndrome. AGG interruptions in CGG repeat tracts were found in most healthy individuals, suggesting a crucial role in preventing disease-prone repeat expansion. Previous biophysics studies emphasize a difference in the secondary structure affected by AGG interruptions. However, the mechanism of how AGG interruptions impede repeat expansion remains elusive. We utilized single-molecule fluorescence resonance energy transfer spectroscopy to investigate the structural dynamics of CGG repeats and their AGG-interrupted variants. Tandem CGG repeats fold into a stem-loop hairpin structure with the capability to undergo a conformational rearrangement to modulate the length of the overhang. However, this conformational rearrangement is much more retarded when two AGG interruptions are present. Considering the significance of hairpin slippage in repeat expansion, we present a molecular basis suggesting that the internal loop created by two AGG interruptions acts as a barrier, obstructing the hairpin slippage reconfiguration. This impediment potentially plays a crucial role in curbing abnormal expansion, thereby contributing to the genomic stability.

Original languageEnglish
Pages (from-to)230-235
Number of pages6
JournalACS Chemical Neuroscience
Volume15
Issue number2
DOIs
Publication statusPublished - 2024 Jan 17

Keywords

  • AGG interruptions
  • Abnormal expansion
  • CGG repeats
  • DNA conformational dynamics
  • Fragile X Syndrome (FXS)
  • Single-molecule FRET
  • Trinucleotide repeat (TNR)

ASJC Scopus subject areas

  • Biochemistry
  • Physiology
  • Cognitive Neuroscience
  • Cell Biology

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