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

Details

Serval ID
serval:BIB_BA1B84ED28C3
Type
Article: article from journal or magazin.
Collection
Publications
Title
Genome-wide demethylation promotes triplet repeat instability independently of homologous recombination.
Journal
DNA Repair
Author(s)
Dion V., Lin Y., Price B.A., Fyffe S.L., Seluanov A., Gorbunova V., Wilson J.H.
ISSN
1568-7864 (Print)
ISSN-L
1568-7856
Publication state
Published
Issued date
2008
Volume
7
Number
2
Pages
313-320
Language
english
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.
Keywords
Adenine Phosphoribosyltransferase/genetics, Animals, Azacitidine/analogs & derivatives, CHO Cells, Cricetinae, Cricetulus, DNA Methylation, DNA Primers/genetics, Genomic Instability/genetics, Recombination, Genetic/genetics, Reverse Transcriptase Polymerase Chain Reaction, Trinucleotide Repeats/genetics
Pubmed
Web of science
Create date
27/02/2014 9:56
Last modification date
20/08/2019 15:28
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