Genome-wide demethylation promotes triplet repeat instability independently of homologous recombination.
DNA Repair (Amst)
; 7(2): 313-20, 2008 Feb 01.
Article
em En
| MEDLINE
| ID: mdl-18083071
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 61 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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Recombinação Genética
/
Repetições de Trinucleotídeos
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Metilação de DNA
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Instabilidade Genômica
Limite:
Animals
Idioma:
En
Ano de publicação:
2008
Tipo de documento:
Article