8X1V

NMR structure of a bimolecular parallel G-quadruplex formed by AAGGG repeats from pathogenic RFC1 gene

Summary for 8X1V

• Entry DOI: 10.2210/pdb8x1v/pdb
• Descriptor: DNA (5'-D(*AP*AP*GP*GP*GP*AP*AP*GP*GP*GP*AP*A)-3') (1 entity in total)
• Functional Keywords: dna, g-quadruplex, aaggg repeats, rfc1 gene
• Biological source: Homo sapiens
• Total number of polymer chains: 2
• Total formula weight: 7619.04

Authors

Wang, Y.,Guo, P.,Han, D. (deposition date: 2023-11-08, release date: 2024-01-17, Last modification date: 2024-05-15)

Primary citation

Wang, Y.,Wang, J.,Yan, Z.,Hou, J.,Wan, L.,Yang, Y.,Liu, Y.,Yi, J.,Guo, P.,Han, D.
Structural investigation of pathogenic RFC1 AAGGG pentanucleotide repeats reveals a role of G-quadruplex in dysregulated gene expression in CANVAS.
Nucleic Acids Res., 52:2698-2710, 2024

PubMed Abstract: An expansion of AAGGG pentanucleotide repeats in the replication factor C subunit 1 (RFC1) gene is the genetic cause of cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS), and it also links to several other neurodegenerative diseases including the Parkinson's disease. However, the pathogenic mechanism of RFC1 AAGGG repeat expansion remains enigmatic. Here, we report that the pathogenic RFC1 AAGGG repeats form DNA and RNA parallel G-quadruplex (G4) structures that play a role in impairing biological processes. We determine the first high-resolution nuclear magnetic resonance (NMR) structure of a bimolecular parallel G4 formed by d(AAGGG)2AA and reveal how AAGGG repeats fold into a higher-order structure composed of three G-tetrad layers, and further demonstrate the formation of intramolecular G4s in longer DNA and RNA repeats. The pathogenic AAGGG repeats, but not the nonpathogenic AAAAG repeats, form G4 structures to stall DNA replication and reduce gene expression via impairing the translation process in a repeat-length-dependent manner. Our results provide an unprecedented structural basis for understanding the pathogenic mechanism of AAGGG repeat expansion associated with CANVAS. In addition, the high-resolution structures resolved in this study will facilitate rational design of small-molecule ligands and helicases targeting G4s formed by AAGGG repeats for therapeutic interventions.

PubMed: 38266156
DOI: 10.1093/nar/gkae032

Experimental method

SOLUTION NMR