Document Detail


Genome-wide demethylation promotes triplet repeat instability independently of homologous recombination.
MedLine Citation:
PMID:  18083071     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Vincent Dion; Yunfu Lin; Brandee A Price; Sharyl L Fyffe; Andrei Seluanov; Vera Gorbunova; John H Wilson
Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  DNA repair     Volume:  7     ISSN:  1568-7864     ISO Abbreviation:  DNA Repair (Amst.)     Publication Date:  2008 Feb 
Date Detail:
Created Date:  2008-01-07     Completed Date:  2008-05-13     Revised Date:  2014-09-16    
Medline Journal Info:
Nlm Unique ID:  101139138     Medline TA:  DNA Repair (Amst)     Country:  Netherlands    
Other Details:
Languages:  eng     Pagination:  313-20     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
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*
Grant Support
ID/Acronym/Agency:
GM 38219/GM/NIGMS NIH HHS; R01 EY011731/EY/NEI NIH HHS; R01 GM038219/GM/NIGMS NIH HHS; R01 GM038219-16/GM/NIGMS NIH HHS; R01 GM038219-17/GM/NIGMS NIH HHS; R01 GM038219-18A1/GM/NIGMS NIH HHS; R01 GM038219-19/GM/NIGMS NIH HHS; R01 GM038219-20/GM/NIGMS NIH HHS; T32 EY 007102/EY/NEI NIH HHS
Chemical
Reg. No./Substance:
0/DNA Primers; 776B62CQ27/decitabine; EC 2.4.2.7/Adenine Phosphoribosyltransferase; M801H13NRU/Azacitidine
Comments/Corrections

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