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Expanded CAG repeats activate the DNA damage checkpoint pathway.

Mayurika Lahiri1, Tanya L Gustafson, Elizabeth R Majors

  • 1Department of Biology, Tufts University, Medford, MA 02155, USA.

Molecular Cell
|July 21, 2004
PubMed
Summary
This summary is machine-generated.

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Expanded CAG repeats trigger DNA damage responses. Yeast gene mutations affecting DNA repair pathways, particularly RAD9, increase trinucleotide repeat instability, highlighting key mechanisms in genetic disease.

Area of Science:

  • Genetics
  • Molecular Biology
  • DNA Repair Mechanisms

Background:

  • Trinucleotide repeats (TNRs) are DNA sequences prone to expansion, leading to genetic disorders and chromosomal instability.
  • Expanded TNRs, particularly CAG repeats, are implicated in various neurodegenerative diseases and DNA breakage events.

Purpose of the Study:

  • To investigate the role of DNA damage response pathways in the stability of expanded CAG trinucleotide repeats.
  • To identify specific genes and pathways involved in sensing and repairing breaks within CAG repeat tracts.

Main Methods:

  • Utilized yeast models with expanded CAG repeat tracts.
  • Assessed the impact of mutations in key DNA damage response genes (MEC1, RAD9, RAD53, RAD17, RAD24, CHK1, DDC2) on CAG repeat fragility and stability.

Related Experiment Videos

  • Quantified rates of CAG repeat fragility and contraction in different mutant backgrounds.

    • Main Results:

    • Expanded CAG repeats activate the DNA damage response.
    • Mutations in MEC1, RAD9, or RAD53 significantly increased CAG repeat fragility, implicating the Rad9 pathway in sensing and repair.
    • RAD17 and RAD24 deletions had a minor effect, suggesting the Rad17-Rad24 pathway is less critical for CAG fragility.
    • CHK1 deletion did not affect CAG fragility, indicating Chk1-mediated G2 arrest is not essential for TNR repair.
    • Absence of Mec1, Ddc2, Rad17, Rad24, or Rad53 increased CAG repeat contractions, highlighting their role in maintaining repeat stability.

    Conclusions:

    • The DNA damage response, particularly signaling through the Rad9 pathway, is crucial for maintaining the integrity of expanded CAG repeat tracts.
    • Components of the checkpoint machinery actively contribute to the stability of expanded CAG sequences, preventing both fragility and contraction.
    • Understanding these mechanisms offers insights into the pathogenesis of TNR-expansion diseases.