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DNA damage induced by polyglutamine-expanded proteins.

Paola Giuliano1, Tiziana De Cristofaro, Adelina Affaitati

  • 1BioGem Consortium, Università 'Federico II', via Pansini 5, 80131 Napoli, Italy.

Human Molecular Genetics
|August 14, 2003
PubMed
Summary

Expanded polyglutamine proteins trigger DNA damage responses via reactive oxygen species, activating ATM/ATR kinases. This activation, observed in Huntington

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Area of Science:

  • Neuroscience
  • Molecular Biology
  • Genetics

Background:

  • Polyglutamine (PolyQ) expansion diseases, such as Huntington's disease and spinocerebellar ataxia type 2 (SCA-2), are characterized by protein aggregation.
  • The precise molecular mechanisms linking PolyQ protein expression to cellular dysfunction remain incompletely understood.

Purpose of the Study:

  • To investigate the cellular response to expanded polyglutamine protein expression.
  • To determine the role of DNA damage response pathways in PolyQ-mediated cellular toxicity.

Main Methods:

  • Development of stable cell lines expressing green fluorescent protein (GFP) fusion proteins with varying polyglutamine repeat lengths under tetracycline control.
  • Analysis of aggregate formation, apoptosis, and DNA damage response activation (e.g., ATM/ATR substrate phosphorylation, H2AX phosphorylation).

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  • Assessment of patient-derived fibroblasts (Huntington's disease, SCA-2) under normal and oxidative stress conditions.

    • Main Results:

    • Expanded polyglutamine (43Q) protein expression led to time-dependent aggregate formation without inducing apoptosis.
    • PolyQ expression activated the ataxia telangiectasia mutated kinase/ATM and Rad3-related kinase (ATM/ATR)-dependent DNA damage response, indicated by ATM substrate phosphorylation.
    • Phosphorylated ATM substrates and H2AX were observed in fibroblasts from Huntington's disease and SCA-2 patients, with increased ATM/ATR phosphorylation under oxidative stress.

    Conclusions:

    • Polyglutamine expansion triggers an ATM/ATR-dependent DNA damage response, mediated by reactive oxygen species accumulation.
    • ATM activation serves as a potential biomarker for monitoring PolyQ diseases in vivo.