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Related Experiment Videos

Cis-elements governing trinucleotide repeat instability in Saccharomyces cerevisiae.

M L Rolfsmeier1, M J Dixon, L Pessoa-Brandão

  • 1Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska 68198-6805, USA.

Genetics
|April 6, 2001
PubMed
Summary

Yeast genetic assays revealed that trinucleotide repeat (TNR) instability has a minimal repeat length threshold and is sequence-specific, similar to humans. These findings demonstrate conserved mechanisms of TNR instability across species.

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Area of Science:

  • Genetics
  • Molecular Biology
  • Genomic Instability

Background:

  • Trinucleotide repeat (TNR) instability in humans is influenced by specific cis-elements, including a minimal repeat length threshold and sequence specificity.
  • The hairpin-forming ability of CNG sequences is hypothesized to drive TNR instability by interfering with DNA repair.
  • The molecular basis of these cis-elements remains unclear due to a lack of direct demonstration in model systems.

Purpose of the Study:

  • To investigate the conserved nature of TNR instability cis-elements by monitoring expansions and contractions in yeast.
  • To determine if a minimal repeat length threshold for TNR mutations exists in a model organism.
  • To assess the role of sequence composition and flap endonuclease in TNR instability.

Main Methods:

Related Experiment Videos

  • Utilized yeast genetic assays to monitor trinucleotide repeat expansions and contractions.
  • Analyzed mutations across various CTG tract lengths and sequence compositions (CNG vs. A-T rich).
  • Examined the impact of flap endonuclease (Rad27p) deficiency on TNR expansion thresholds.

Main Results:

  • A threshold of approximately 15-17 repeats was identified for both CTG expansions and contractions in yeast.
  • CNG/GNC sequences exhibited high mutation rates, while A-T rich sequences were more stable, supporting a hairpin-mediated instability model.
  • The absence of flap endonuclease (Rad27p) did not significantly alter the expansion threshold, suggesting flap processing is not critical for threshold determination.
  • Expansions and contractions occurred at similar rates for CTG tracts between 15 and 25 repeats.

Conclusions:

  • Key cis-elements governing human TNR instability, including repeat length thresholds and sequence specificity, are functional in yeast.
  • The findings support a hairpin-mediated mechanism for TNR instability, conserved across species.
  • Expansions constitute a significant portion of TNR mutations in yeast, particularly within the identified threshold range.