Human Molecular Genetics Advance Access published online on July 22, 2003
Human Molecular Genetics, doi:10.1093/hmg/ddg242
© 2003 by Oxford University Press
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1 BioGem Consortium, Department of Molecular and Cellular Biology and Pathology, Federico II University, Naples, Italy
* To whom correspondence should be addressed. E-mail: avvedim{at}unina.it.
We have developed stable cell lines expressing GFP fusion proteins containing the CAG 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 43 CAG expanded protein strongly activated the ATM/ATR dependent DNA damage response, as shown by selective phosphorylation of ATM substrates. This activation was dependent on 43 CAG protein expression, was reversible and sensitive to caffeine and reducing agents. Similarly, we found phosphorylated ATM substrates in fibroblasts from HD 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 induce ATM/ATR dependent DNA damage response through accumulation of ROS. ATM activation can be used to monitor the disease in vivo. Key Words:
CAG expanded proteins; DNA damage; ATM
Article
DNA damage induced by CAG-expanded proteins
2 IEOS-CNR, Department of Molecular and Cellular Biology and Pathology, Federico II University, Naples, Italy
3 Department of Molecular and Cellular Biology and Pathology, Federico II University, Naples, Italy
4 Department of Neurology, Federico II University, Naples, Italy
5 Dipartimento di Biologia e Patologia Molecolare e Cellulare, Università "Federico II", via Pansini 5, 80131, Napoli, Italy
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