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, Ellen Fanning

Research output: Contribution to journalArticle

40 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)426-437
Number of pages12
JournalMolecular and Cellular Biology
Volume27
Issue number2
DOIs
StatePublished - Jan 2007
Externally publishedYes

Fingerprint

Fragile X Mental Retardation Protein
Replication Origin
DNA Replication
Genetic Promoter Regions
Intellectual Disability
Genes
Fragile X Syndrome
Fibroblasts
Trinucleotide Repeats
Transformed Cell Line
5' Untranslated Regions
DNA Methylation
Chromatin
Maintenance

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cell Biology

Cite this

An origin of DNA replication in the promoter region of the human fragile X mental retardation (FMR1) gene. / Gray, Steven J.; Gerhardt, Jeannine; Doerfler, Walter; Small, Lawrence E.; Fanning, Ellen.

In: Molecular and Cellular Biology, Vol. 27, No. 2, 01.2007, p. 426-437.

Research output: Contribution to journalArticle

Gray, Steven J. ; Gerhardt, Jeannine ; Doerfler, Walter ; Small, Lawrence E. ; Fanning, Ellen. / An origin of DNA replication in the promoter region of the human fragile X mental retardation (FMR1) gene. In: Molecular and Cellular Biology. 2007 ; Vol. 27, No. 2. pp. 426-437.
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