Article

Genome-wide demethylation promotes triplet repeat instability independently of homologous recombination.

Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
DNA Repair (Impact Factor: 3.36). 03/2008; 7(2):313-20. DOI: 10.1016/j.dnarep.2007.11.002
Source: PubMed

ABSTRACT Trinucleotide repeat instability is intrinsic to a family of human neurodegenerative diseases. The mechanism leading to repeat length variation is unclear. We previously showed that treatment with the demethylating agent 5-aza-2'-deoxycytidine (5-aza-CdR) dramatically increases triplet repeat instability in mammalian cells. Based on previous reports that demethylation increases homologous recombination (HR), and our own observations that HR destabilizes triplet repeats, we hypothesized that demethylation alters repeat stability by stimulating HR. Here, we test that hypothesis at the adenosine phosphoribosyl transferase (Aprt) locus in CHO cells, where CpG demethylation and HR have both been shown to increase CAG repeat instability. We find that the rate of HR at the Aprt locus is not altered by demethylation. The spectrum of recombinants, however, was shifted from the usual 6:1 ratio of conversions to crossovers to more equal proportions in 5-aza-CdR-treated cells. The subtle influences of demethylation on HR at the Aprt locus are not sufficient to account for its dramatic effects on repeat instability. We conclude that 5-aza-CdR promotes triplet repeat instability independently of HR.

0 Bookmarks
 · 
90 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Many groups are actively investigating how the epigenetic state relates to environmental exposures and development of disease, including cancer. There are myriad choices for capturing and measuring the epigenetic state of a tissue, ranging from assessing the total methyl-CpG content to array-based platforms that simultaneously probe hundreds of thousands of CpG loci. There is an emerging literature that uses CpG methylation at repetitive sequences, including LINE-1 (long interspersed nuclear element-1) elements, to capture the epigenomic state. We explored the complexity of using CpG methylation at repetitive sequences in epidemiology and translational medical research and suggest needed avenues of research to clarify its meaning and utility. Among the most urgent avenues of research is the need for prospective studies to eliminate the possibilities of reverse causality, and development of new LINE-1 assays that capture both class of LINE-1 element and copy number.
    Environmental Health Perspectives 06/2011; 119(11):1528-33. DOI:10.1289/ehp.1103423 · 7.26 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: A coal-based activated carbon was used to adsorb nitric oxide (NO) and SO2 at temperatures between 20-140°C. At a relative NO/SO2 ratio of 40/1, the rate of NO uptake and the conversion of NO-to-NO2 was decreased by approximately 15% as compared to the case when no SO2 was present. Adsorbed NO2 consisted of two species, the more strongly bound of which could be removed by desorption at temperatures between 100-150°C. Adsorbed SO2 also consisted of two species, the more strongly bound of which required a temperature of 300°C to desorb. The concentration of the more weakly held SO2 decreased in the presence of adsorbed NO2 while the overall concentration of adsorbed SO2 increased in the presence of NO2 as compared to without NO2. The data suggest that the sites which catalyze NO -> NO2 are either poisoned or eliminated by adsorbed SO2.
  • [Show abstract] [Hide abstract]
    ABSTRACT: The Fragile X-associated disorders (FXDs) and Friedreich ataxia (FRDA) are genetic conditions resulting from expansion of a trinucleotide repeat in a region of the affected gene that is transcribed but not translated. In the case of the FXDs, pathology results from expansion of CGG•CCG-repeat tract in the 5' UTR of the FMR1 gene, while pathology in FRDA results from expansion of a GAA•TTC-repeat in intron 1 of the FXN gene. Expansion occurs during gametogenesis or early embryogenesis by a mechanism that is not well understood. Associated Expansion then produces disease pathology in various ways that are not completely understood either. In the case of the FXDs, alleles with 55-200 repeats express higher than normal levels of a transcript that is thought to be toxic, while alleles with >200 repeats are silenced. In addition, alleles with >200 repeats are associated with a cytogenetic abnormality known as a fragile site, which is apparent as a constriction or gap in the chromatin that is seen when cells are grown in presence of inhibitors of thymidylate synthase. FRDA alleles show a deficit of the FXN transcript. This review will address the role of repeat-mediated chromatin changes in these aspects of FXD and FRDA disease pathology. This article is part of a Special Issue entitled: Chromatin in time and space.
    Biochimica et Biophysica Acta 01/2012; 1819(7):802-10. DOI:10.1016/j.bbagrm.2011.12.009 · 4.66 Impact Factor

Full-text (2 Sources)

Download
43 Downloads
Available from
May 22, 2014