Abstract
We have generated an inducible transgenic mouse model, which expresses a mutated version of UNG1 (mutUNG1) that removes thymine, in addition to uracil from mitochondrial DNA. The abasic-sites (AP-sites) generated by removal of thymine or uracil are a threat to genomic integrity, and are particularly harmful in mitochondria due to inhibition of mitochondrial DNA polymerase. MutUNG1, accompanied by a luciferase reporter-gene, is controlled by the Tet-on system. Transgene expression is spatially regulated by the forebrain specific CaMKIIα-promoter, and temporally by the addition of doxycycline. Mice harboring this transgene develop compromised mitochondrial dynamics, neurodegeneration and impaired behavior.
Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.
MeSH terms
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Animals
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DNA Damage*
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DNA, Mitochondrial / genetics
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DNA, Mitochondrial / metabolism*
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DNA-Directed DNA Polymerase / genetics
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DNA-Directed DNA Polymerase / metabolism
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Genome, Mitochondrial / genetics
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Genomic Instability / genetics
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Inhibitor of Growth Protein 1
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Intracellular Signaling Peptides and Proteins / genetics
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Mice
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Mice, Transgenic
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Mitochondrial Proteins / genetics
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Mitochondrial Proteins / metabolism*
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Models, Biological*
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Mutation*
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Nerve Tissue Proteins / genetics
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Nerve Tissue Proteins / metabolism*
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Neurons / metabolism*
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Neurons / pathology
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Nuclear Proteins / biosynthesis*
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Nuclear Proteins / genetics
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Prosencephalon / metabolism*
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Prosencephalon / pathology
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Tumor Suppressor Proteins / biosynthesis*
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Tumor Suppressor Proteins / genetics
Substances
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DNA, Mitochondrial
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Ing1 protein, mouse
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Inhibitor of Growth Protein 1
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Intracellular Signaling Peptides and Proteins
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Mitochondrial Proteins
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Nerve Tissue Proteins
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Nuclear Proteins
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Tumor Suppressor Proteins
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DNA-Directed DNA Polymerase