ArticleNucleic acids research2024
Structural investigation of pathogenic RFC1 AAGGG pentanucleotide repeats reveals a role of G-quadruplex in dysregulated gene expression in CANVAS.
Article in Nucleic acids research, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed, 19 citations in OpenAlex.
- Tandem repeats in human brain evolution and disease susceptibility.Molecules and cells · 2026Review
- Condensate protein aggregation in ALS/FTD is regulated by GGGGCC-repeat RNA scaffolds.Nature structural & molecular biology · 2026Article
- Repeat-associated ataxias in a German patient cohort analysed by targeted parallel long-read sequencing.Brain : a journal of neurology · 2026Article
- The Tale of the Guanosine Tract in Repeat Expansion Disorders.Molecular neurobiology · 2026Review
- Pentanucleotide guanine-rich WGGGW repeats, including CANVAS AGGGA repeats, form a variety of noncanonical structures.Nucleic acids research · 2026Article
- From loops to caps: discriminating peptide binding to distinct G-quadruplex tetrads using 5-furyl-2'-deoxyuridine fluorescent probes.RSC chemical biology · 2026Article
- FGF14 repeat length and mosaic interruptions: modifiers of spinocerebellar ataxia 27B?Brain : a journal of neurology · 2025Article
- Emerging drivers of DNA repeat expansions.Biochemical Society transactions · 2025Review
- RFC1 regulates the expansion of neural progenitors in the developing zebrafish cerebellum.Nature communications · 2025Article
- Structural Insights into an Antiparallel Chair-Type G-Quadruplex From the Intron of NOP56 Oncogene.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Long-read sequencing revealed complex biallelic pentanucleotide repeat expansions in RFC1-related Parkinson's disease.NPJ Parkinson's disease · 2025Article
- Triplex H-DNA structure: the long and winding road from the discovery to its role in human disease.NAR molecular medicine · 2024Article
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Authors and funding
10 authors at 4 institutions in 1 country.
Funding
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.
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