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Human Molecular Genetics Advance Access originally published online on July 22, 2003
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Human Molecular Genetics, 2003, Vol. 12, No. 18 2301-2309
DOI: 10.1093/hmg/ddg242
© 2003 Oxford University Press

DNA damage induced by polyglutamine-expanded proteins

Paola Giuliano1, Tiziana de Cristofaro2, Adelina Affaitati1, Grazia M. Pizzulo1, Antonio Feliciello3, Chiara Criscuolo4, Giuseppe De Michele4, Alessandro Filla4, Enrico V. Avvedimento3,* and Stelio Varrone3

1BioGem Consortium and 2IEOS-CNR c/o Department of Molecular and Cellular Biology and Pathology, 3Department of Molecular and Cellular Biology and Pathology and 4Department of Neurology, Federico II University, Naples, Italy

Received April 17, 2003; Accepted June 11, 2003

We have developed stable cell lines expressing green fluorescent protein fusion proteins containing polyglutamine repeats of various lengths under tetracycline control. The expression of the expanded (43Q) repeat protein resulted in aggregate formation in a time-dependent fashion. The accumulation of aggregates did not induce apoptosis, although the survival of these cells was critically dependent on the presence of serum and growth factors. However, the expression of 43Q expanded protein strongly activated the ataxia telangiectasia mutated kinase/ATM and Rad3-related kinase (ATM/ATR)-dependent DNA damage response, as shown by selective phosphorylation of ATM substrates. This activation was dependent on 43 CAG protein expression, reversible and sensitive to caffeine and reducing agents. Similarly, we found phosphorylated ATM substrates in fibroblasts from Huntington's disease or SCA-2 patients. Oxidative stress induced accumulation of ATM/ATR phosphorylated protein in HD and SCA-2 patients, but not in normal controls. Furthermore, a significant phosphorylation of H2AX was shown by fibroblasts from patients. We conclude that polyglutamine induces ATM/ATR-dependent DNA damage response through accumulation of reactive oxygen species. ATM activation can be used to monitor the disease in vivo.

* To whom correspondence should be addressed at: Dipartimento di Biologia e Patologia Molecolare e Cellulare, Università ‘Federico II’, via Pansini 5, 80131, Napoli, Italy. Tel: +39 817463251; Fax: +39 817463252; Email: avvedim{at}unina.it


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