Role of context in RNA structure: flanking sequences reconfigure CAG motif folding in huntingtin exon 1 transcripts

Biochemistry. 2013 Nov 19;52(46):8219-25. doi: 10.1021/bi401129r. Epub 2013 Nov 7.

Abstract

The length of the CAG-repeat region in the huntingtin mRNA is predictive of Huntington's disease. Structural studies of CAG-repeat-containing RNAs suggest that these sequences form simple hairpin structures; however, in the context of the full-length huntingtin mRNA, CAG repeats may form complex structures that could be targeted for therapeutic intervention. We examined the structures of transcripts spanning the first exon of the huntingtin mRNA with both healthy and disease-prone repeat lengths. In transcripts with 17-70 repeats, the CAG sequences base paired extensively with nucleotides in the 5' UTR and with conserved downstream sequences including a CCG-repeat region. In huntingtin transcripts with healthy numbers of repeats, the previously observed CAG hairpin was either absent or short. In contrast, in transcripts with disease-associated numbers of repeats, a CAG hairpin was present and extended from a three-helix junction. Our findings demonstrate the profound importance of sequence context in RNA folding and identify specific structural differences between healthy and disease-inducing huntingtin alleles that may be targets for therapeutic intervention.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 5' Untranslated Regions / physiology
  • Exons
  • Humans
  • Huntingtin Protein
  • Huntington Disease / genetics
  • Nerve Tissue Proteins / chemistry*
  • RNA / genetics
  • RNA / metabolism*
  • RNA Folding
  • RNA, Messenger / chemistry*
  • RNA, Messenger / genetics
  • Ribonuclease T1 / metabolism
  • Trinucleotide Repeat Expansion*

Substances

  • 5' Untranslated Regions
  • HTT protein, human
  • Huntingtin Protein
  • Nerve Tissue Proteins
  • RNA, Messenger
  • RNA
  • Ribonuclease T1