Suppression of Uracil-DNA Glycosylase Induces Neuronal Apoptosis
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 und...
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Published in | The Journal of biological chemistry Vol. 279; no. 42; pp. 43952 - 43960 |
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Main Authors | , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
American Society for Biochemistry and Molecular Biology
15.10.2004
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Subjects | |
Online Access | Get full text |
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Summary: | 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. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 0021-9258 1083-351X |
DOI: | 10.1074/jbc.M408025200 |