Journal Article

DNA damage induced by polyglutamine-expanded proteins

Paola Giuliano, Tiziana de Cristofaro, Adelina Affaitati, Grazia M. Pizzulo, Antonio Feliciello, Chiara Criscuolo, Giuseppe De Michele, Alessandro Filla, Enrico V. Avvedimento and Stelio Varrone

in Human Molecular Genetics

Volume 12, issue 18, pages 2301-2309
Published in print September 2003 | ISSN: 0964-6906
Published online September 2003 | e-ISSN: 1460-2083 | DOI:
DNA damage induced by polyglutamine-expanded proteins

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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.

Journal Article.  6021 words.  Illustrated.

Subjects: Genetics and Genomics

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