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A single nucleotide polymorphism or SNP is a single nucleotide variation at a specific genomic position in a large population. It is the most prevalent type of sequence variation found in the human genome. Point mutations that occur in more than 1% of the population qualify as SNPs. These are present once every 1000 nucleotides on an average in the human genome. Replacement of a purine with another purine (A/G) or a pyrimidine with another pyrimidine (C/T) is known as a transition. In contrast,...
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Riboswitches are non-coding mRNA domains that regulate the transcription and translation of downstream genes without the help of proteins. Riboswitches bind directly to a metabolite and can form unique stem-loop or hairpin structures in response to the amount of the metabolite present. They have two distinct regions – a metabolite-binding aptamer and an expression platform.
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Pathogenic SNPs Affect Both RNA and DNA G-Quadruplexes' Responses to Ligands.

Marc-Antoine Turcotte1, Jean-Pierre Perreault1

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Single nucleotide polymorphisms (SNPs) impact guanine-quadruplex (G4) structures and their interactions with ligands. Understanding these genetic variations is crucial for selecting effective G4 ligands in G-rich gene research.

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Area of Science:

  • Genetics
  • Molecular Biology
  • Biochemistry

Background:

  • Single nucleotide polymorphisms (SNPs) are common genetic variations affecting DNA and RNA structures.
  • Guanine-quadruplex (G4) structures are formed by stacked guanine tetrads.
  • The influence of SNPs on G4 ligand interactions remains largely unexplored.

Purpose of the Study:

  • To investigate the impact of SNPs on the binding efficacy and specificity of G4 ligands.
  • To demonstrate how SNPs modulate the response of DNA and RNA G4s to various ligands.
  • To establish a proof-of-concept using SNPs within the α-synuclein gene.

Main Methods:

  • Bioinformatic prediction of G4 structures.
  • Inclusion of identified SNPs within the α-synuclein gene.
  • Assessment of interactions between six established G4 ligands (Phen-DC3, PDS, 360A, RHPS4, BRACO19, TMPyP4) and SNP-containing G4s.
  • Evaluation of ligand effects on G4 structure and polymerase stalling.

Main Results:

  • SNPs were shown to differentially modulate both DNA and RNA G4 structures in response to ligands.
  • The binding efficacy and specificity of the tested G4 ligands varied significantly across different SNPs.
  • Ligand-induced changes in G4 structure and polymerase stalling were observed to be SNP-dependent.

Conclusions:

  • SNPs can significantly alter the behavior of G4 structures and their interaction with ligands.
  • The choice of G4 ligand is critical when an SNP is present in a G-rich gene.
  • This study underscores the importance of considering genetic variations like SNPs in G4-targeted therapeutic strategies.