New insights into repeat instability: Role of RNA•DNA hybrids

Elizabeth I. McIvor, Urszula Polak, Marek Napierala

Research output: Contribution to journalReview articlepeer-review

30 Scopus citations

Abstract

Expansion of tandem repeat sequences is responsible for more than 20 human diseases. Several cis elements and trans factors involved in repeat instability (expansion and contraction) have been identified. However no comprehensive model explaining large intergenerational or somatic changes of the length of the repeating sequences exists. Several lines of evidence, accumulated from different model studies, indicate that transcription through repeat sequences is an important factor promoting their instability. The persistent interaction between transcription template DNA and nascent RNA (RNA•DNA hybrids, R loops) was shown to stimulate genomic instability. Recently, we demonstrated that cotranscriptional RNA•DNA hybrids are preferentially formed at GC-rich trinucleotide and tetranucleotide repeat sequences in vitro as well as in human genomic DNA. Additionally, we showed that cotranscriptional formation of RNA•DNA hybrids at CTG•CAG and GAA•TTC repeats stimulate instability of these sequences in both E. coli and human cells. Our results suggest that persistent RNA•DNA hybrids may also be responsible for other downstream effects of expanded trinucleotide repeats, including gene silencing. Considering the extent of transcription through the human genome as well as the abundance of GC-rich and/or non-canonical DNA structure forming tandem repeats, RNA•DNA hybrids may represent a common mutagenic conformation. Hence, R loops are potentially attractive therapeutic targets in diseases associated with genomic instability.

Original languageEnglish (US)
Pages (from-to)551-558
Number of pages8
JournalRNA Biology
Volume7
Issue number5
DOIs
StatePublished - 2010
Externally publishedYes

Keywords

  • R loops
  • Repeat expansion diseases
  • RNase H
  • RNA•DNA hybrids
  • Transcription-induced repeat instability
  • Triplet repeats

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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