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PMID: 17450122 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, N.I.H., Intramural Research Support, Non-U.S. Gov't

OGG1 initiates age-dependent CAG trinucleotide expansion in somatic cells.

Nature ·Vol. 447 ·No. 7143 ·2007-05-24 ·Pages 447-52

Kovtun IV, Liu Y, Bjoras M, Klungland A, Wilson SH, McMurray CT

Abstract

Although oxidative damage has long been associated with ageing and neurological disease, mechanistic connections of oxidation to these phenotypes have remained elusive. Here we show that the age-dependent somatic mutation associated with Huntington's disease occurs in the process of removing oxidized base lesions, and is remarkably dependent on a single base excision repair enzyme, 7,8-dihydro-8-oxoguanine-DNA glycosylase (OGG1). Both in vivo and in vitro results support a 'toxic oxidation' model in which OGG1 initiates an escalating oxidation-excision cycle that leads to progressive age-dependent expansion. Age-dependent CAG expansion provides a direct molecular link between oxidative damage and toxicity in post-mitotic neurons through a DNA damage response, and error-prone repair of single-strand breaks.

MeSH Terms
Aging/genetics Animals Cell Line DNA Breaks, Single-Stranded DNA Damage DNA Glycosylases/deficiency,genetics,metabolism DNA Repair/genetics Female Guanosine/analogs & derivatives,metabolism Humans Huntington Disease/genetics Male Mice Models, Genetic Neurons/metabolism Oxidation-Reduction Trinucleotide Repeat Expansion/genetics
Chemicals
Guanosine 8-hydroxyguanosine DNA Glycosylases Ogg1 protein, mouse
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Kovtun Irina V
Department of Pharmacology and Experimental Therapeutics, Mayo Clinic and Foundation, 200 First Street SW, Rochester, Minnesota 55905, USA.
Liu Yuan
Bjoras Magnar
Klungland Arne
Wilson Samuel H
McMurray Cynthia T
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Article Info
Journal
Nature
Abbr.
Nature
ISSN
1476-4687
DOI
10.1038/nature05778
Published
2007-05-24
Epub
2007-00-22
Pages
447-52
Language
English
Region
England
NLM ID
0410462
PMCID
PMC2681094
Subset
IM
Grants
Intramural NIH HHS · Z01 ES050158-11 · United States
NIGMS NIH HHS · R01 GM066359-05A1 · United States
NIGMS NIH HHS · R01 GM066359 · United States
NINDS NIH HHS · R01 NS040738 · United States
NINDS NIH HHS · R01 NS040738-05 · United States
External Links
PubMed source DOI: 10.1038/nature05778 PMC Full Text View journal details
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