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Molecular and Cellular Biology, January 2007, p. 426-437, Vol. 27, No. 2
0270-7306/07/$08.00+0     doi:10.1128/MCB.01382-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

An Origin of DNA Replication in the Promoter Region of the Human Fragile X Mental Retardation (FMR1) Gene ^,

Steven J. Gray ,^, Jeannine Gerhardt, Walter Doerfler,^¶ Lawrence E. Small, and Ellen Fanning^*

Department of Biological Sciences and Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, Tennessee 37235

Received 27 July 2006/ Returned for modification 21 August 2006/ Accepted 30 October 2006

Fragile X syndrome, the most common form of inherited mental retardation in males, arises when the normally stable 5 to 50 CGG repeats in the 5' untranslated region of the fragile X mental retardation protein 1 (FMR1) gene expand to over 200, leading to DNA methylation and silencing of the FMR1 promoter. Although the events that trigger local CGG expansion remain unknown, the stability of trinucleotide repeat tracts is affected by their position relative to an origin of DNA replication in model systems. Origins of DNA replication in the FMR1 locus have not yet been described. Here, we report an origin of replication adjacent to the FMR1 promoter and CGG repeats that was identified by scanning a 35-kb region. Prereplication proteins Orc3p and Mcm4p bind to chromatin in the FMR1 initiation region in vivo. The position of the FMR1 origin relative to the CGG repeats is consistent with a role in repeat maintenance. The FMR1 origin is active in transformed cell lines, fibroblasts from healthy individuals, fibroblasts from patients with fragile X syndrome, and fetal cells as early as 8 weeks old. The potential role of the FMR1 origin in CGG tract instability is discussed.

Published ahead of print on 13 November 2006.

Supplemental material for this article may be found at http://mcb.asm.org/.

Co-first authors.

Present address: Gene Therapy Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599.

^¶ Permanent address: Institute for Clinical and Molecular Virology, Universität Erlangen, Schlossgarten 4, 91054 Erlangen, Germany.

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