Nucleic Acids Research Advance Access originally published online on August 26, 2009
Nucleic Acids Research 2009 37(19):6371-6377; doi:10.1093/nar/gkp666
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Nucleic Acids Research, 2009, Vol. 37, No. 19 6371-6377
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 |
ATM and ATR protect the genome against two different types of tandem repeat instability in Fragile X premutation mice
1Laboratory of Molecular and Cellular Biology, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892-0830, USA and 2Institute of Biomedical and Clinical Sciences, Peninsula College of Medicine and Dentistry, University of Exeter, EX1 2LU Devon, UK
*To whom correspondence should be addressed. Tel: +1 301 496 2189; Fax: +1 301 402 0053; Email: ku{at}helix.nih.gov
Received March 10, 2009. Accepted July 28, 2009.
Expansion of a tandem repeat tract is responsible for the Repeat Expansion diseases, a group of more than 20 human genetic disorders that includes those like Fragile X (FX) syndrome that result from repeat expansion in the FMR1 gene. We have previously shown that the ATM and Rad3-related (ATR) checkpoint kinase protects the genome against one type of repeat expansion in a FX premutation mouse model. By crossing the FX premutation mice to Ataxia Telangiectasia-Mutated (Atm) mutant mice, we show here that ATM also prevents repeat expansion. However, our data suggest that the ATM-sensitive mechanism is different from the ATR-sensitive one. Specifically, the effect of the ATM deficiency is more marked when the premutation allele is paternally transmitted and expansions occur more frequently in male offspring regardless of the Atm genotype of the offspring. The gender effect is most consistent with a repair event occurring in the early embryo that is more efficient in females, perhaps as a result of the action of an X-linked DNA repair gene. Our data thus support the hypothesis that two different mechanisms of FX repeat expansion exist, an ATR-sensitive mechanism seen on maternal transmission and an ATM-sensitive mechanism that shows a male expansion bias.