Suppression of uracil-DNA glycosylase induces neuronal apoptosis

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

Research output: Contribution to journalArticle

Abstract

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 β-synthase knockout mice, a model for hyperhomocysteinemia, suggesting that one-carbon metabolism impairment and uracil misincorporation can induce the up-regulation of UNG expression.

Original languageEnglish (US)
Pages (from-to)43952-43960
Number of pages9
JournalJournal of Biological Chemistry
Volume279
Issue number42
DOIs
StatePublished - Oct 15 2004

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ASJC Scopus subject areas

  • Biochemistry

Cite this

Kruman, I. I., Schwartz, E., Kruman, Y., Cutler, R. G., Zhu, X., Greig, N. H., & Mattson, M. P. (2004). Suppression of uracil-DNA glycosylase induces neuronal apoptosis. Journal of Biological Chemistry, 279(42), 43952-43960. https://doi.org/10.1074/jbc.M408025200