Nucleic Acids Research Advance Access originally published online on May 21, 2009
Nucleic Acids Research 2009 37(13):4385-4392; doi:10.1093/nar/gkp391
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Nucleic Acids Research, 2009, Vol. 37, No. 13 4385-4392
© Published by Oxford University Press 2009
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Genome Integrity, Repair and Replication |
The role of DNA damage response pathways in chromosome fragility in Fragile X syndrome
1Section on Gene Structure and Disease, Laboratory of Molecular and Cellular Biology, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892-0830, USA 2Istituto di Neurobiologia e Medicina Molecolare, CNR, Via del Fosso del Fiorano, 64, 00143 Rome, Italy and 3Laboratory of Molecular Pharmacology, CCR, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-4264, USA
*To whom correspondence should be addressed. Tel/Fax: +1 301 496 2189; Email: ku{at}helix.nih.gov
Received January 14, 2009. Revised April 3, 2009. Accepted April 30, 2009.
FRAXA is one of a number of fragile sites in human chromosomes that are induced by agents like fluorodeoxyuridine (FdU) that affect intracellular thymidylate levels. FRAXA coincides with a >200 CGG•CCG repeat tract in the 5' UTR of the FMR1 gene, and alleles prone to fragility are associated with Fragile X (FX) syndrome, one of the leading genetic causes of intellectual disability. Using siRNA depletion, we show that ATR is involved in protecting the genome against FdU-induced chromosome fragility. We also show that FdU increases the number of 
-H2AX foci seen in both normal and patient cells and increases the frequency with which the FMR1 gene colocalizes with these foci in patient cells. In the presence of FdU and KU55933, an ATM inhibitor, the incidence of chromosome fragility is reduced, suggesting that ATM contributes to FdU-induced chromosome fragility. Since both ATR and ATM are involved in preventing aphidicolin-sensitive fragile sites, our data suggest that the lesions responsible for aphidicolin-induced and FdU-induced fragile sites differ. FRAXA also displays a second form of chromosome fragility in absence of FdU, which our data suggest is normally prevented by an ATM-dependent process.