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J. Biol. Chem., Vol. 279, Issue 42, 43952-43960, October 15, 2004

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Suppression of Uracil-DNA Glycosylase Induces Neuronal Apoptosis^*

Inna I. Kruman, Elena Schwartz¶, Yuri Kruman||, Roy G. Cutler||, Xiaoxiang Zhu||, Nigel H. Greig||, and Mark P. Mattson||**

From the Sun Health Research Institute, Sun City, Arizona 85351, ^¶Laboratory of Molecular Growth Regulation, NICHD, National Institutes of Health, Bethesda, Maryland 20892, the ^||Laboratory of Neurosciences, National Institute on Aging Gerontology Research Center, Baltimore, Maryland 21224, and the ^**Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205

A chronic imbalance in DNA precursors, caused by one-carbon metabolism impairment, can result in a deficiency of DNA repair and increased DNA damage. Although indirect evidence suggests that DNA damage plays a role in neuronal apoptosis and in the pathogenesis of neurodegenerative disorders, the underlying mechanisms are poorly understood. In particular, very little is known about the role of base excision repair of misincorporated uracil in neuronal survival. To test the hypothesis that repair of DNA damage associated with uracil misincorporation is critical for neuronal survival, we employed an antisense (AS) oligonucleotide directed against uracil-DNA glycosylase encoded by the UNG gene to deplete UNG in cultured rat hippocampal neurons. AS, but not a scrambled control oligonucleotide, induced apoptosis, which was associated with DNA damage analyzed by comet assay and up-regulation of p53. UNG mRNA and protein levels were decreased within 30 min and were undetectable within 6-9 h of exposure to the UNG AS oligonucleotide. Whereas UNG expression is significantly higher in proliferating as compared with nonproliferating cells, such as neurons, the levels of UNG mRNA were increased in brains of cystathionine -synthase knockout mice, a model for hyperhomocysteinemia, suggesting that one-carbon metabolism impairment and uracil misincorporation can induce the up-regulation of UNG expression.

Received for publication, July 15, 2004

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Sun Health Research Institute, 10515 Santa Fe Dr., Sun City, AZ 85351. Tel.: 623-876-5328; Fax: 623-876-5695; E-mail: inna.kruman{at}sunhealth.org.

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