Structural polymorphism of the nucleic acids in pentanucleotide repeats associated with the neurological disorder CANVAS

J Biol Chem. 2024 Apr;300(4):107138. doi: 10.1016/j.jbc.2024.107138. Epub 2024 Mar 5.

Abstract

Short tandem repeats are inherently unstable during DNA replication depending on repeat length, and the expansion of the repeat length in the human genome is responsible for repeat expansion disorders. Pentanucleotide AAGGG and ACAGG repeat expansions in intron 2 of the gene encoding replication factor C subunit 1 (RFC1) cause cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS) and other phenotypes of late-onset cerebellar ataxia. Herein, we reveal the structural polymorphism of the RFC1 repeats associated with CANVAS in vitro. Single-stranded AAGGG repeat DNA formed a hybrid-type G-quadruplex, whereas its RNA formed a parallel-type G-quadruplex with three layers. The RNA of the ACAGG repeat formed hairpin structure comprising C-G and G-C base pairs with A:A and GA:AG mismatched repeats. Furthermore, both pathogenic repeat RNAs formed more rigid structures than those of the nonpathogenic repeat RNAs. These findings provide novel insights into the structural polymorphism of the RFC1 repeats, which may be closely related to the disease mechanism of CANVAS.

Keywords: G-quadruplex; biophysics; genetic disease; neurodegenerative disease; nucleic acid structure.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cerebellar Ataxia* / genetics
  • Cerebellar Ataxia* / metabolism
  • DNA Repeat Expansion*
  • G-Quadruplexes
  • Humans
  • Microsatellite Repeats
  • Peripheral Nervous System Diseases* / genetics
  • Peripheral Nervous System Diseases* / metabolism
  • Polymorphism, Genetic
  • RNA / chemistry
  • RNA / genetics
  • RNA / metabolism
  • Replication Protein C* / chemistry
  • Replication Protein C* / genetics
  • Replication Protein C* / metabolism
  • Vestibular Diseases* / genetics
  • Vestibular Diseases* / metabolism

Substances

  • Replication Protein C
  • RFC1 protein, human
  • RNA
  • CANVAS syndrome