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Nucleic Acids Research Advance Access first published online on December 26, 2007
This version published online on January 7, 2008
Nucleic Acids Research, doi:10.1093/nar/gkm1136
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© 2008 The Author(s)
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.

Molecular Biology

ATR protects the genome against CGG·CGG-repeat expansion in Fragile X premutation mice

Ali Entezam and Karen Usdin*

Section 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

*To whom correspondence should be addressed. Tel: +1 301 496 2189; Fax: +1 301 402 0053; Email: ku{at}helix.nih.gov

Received October 1, 2007. Revised December 6, 2007. Accepted December 6, 2007.

Fragile X mental retardation syndrome is a repeat expansion disease caused by expansion of a CGG·CGG-repeat tract in the 5' UTR of the FMR1 gene. In humans, small expansions occur more frequently on paternal transmission while large expansions are exclusively maternal in origin. It has been suggested that expansion is the result of aberrant DNA replication, repair or recombination. To distinguish amongst these possibilities we crossed mice containing 120 CGG·CGG-repeats in the 5' UTR of the mouse Fmr1 gene to mice with mutations in ATR, a protein important in the cellular response to stalled replication forks and bulky DNA lesions. We show here that ATR heterozygosity results in increased expansion rates of maternally, but not paternally, transmitted alleles. In addition, age-related somatic expansions occurred in mice of both genders that were not seen in ATR wild-type animals. Some ATR-sensitive expansion occurs in postmitotic cells including haploid gametes suggesting that aberrant DNA repair is responsible. Our data suggest that two mechanisms of repeat expansion exist that may explain the small and large expansions seen in humans. In addition, our data provide an explanation for the maternal bias of large expansions in humans and the lower incidence of these expansions in mice.


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[Abstract] [Full Text] [PDF]


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