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J. Biol. Chem., Vol. 277, Issue 47, 44932-44937, November 22, 2002
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From the Oxidative damage to mitochondrial DNA (mtDNA) has
been suggested to be a key factor in the etiologies of many diseases
and in the normal process of aging. Although the presence of a repair system to remove this damage has been demonstrated, the mechanisms involved in this repair have not been well defined. In an effort to
better understand the physiological role of recombinant 8-oxoguanine DNA glycosylase/apurinic lyase (OGG1) in mtDNA repair, we constructed an expression vector containing the gene for OGG1 downstream of the
mitochondrial localization sequence from manganese-superoxide dismutase. This gene construct was placed under the control of a
tetracycline-regulated promoter. Transfected cells that conditionally expressed OGG1 in the absence of the tetracycline analogue doxycycline and targeted this recombinant protein to mitochondria were generated. Western blots of mitochondrial extracts from vector- and
OGG1-transfected clones with and without doxycycline revealed that
removal of doxycycline for 4 days caused an approximate 8-fold increase
in the amount of OGG1 protein in mitochondria. Enzyme activity assays
and DNA repair studies showed that the
doxycycline-dependent recombinant OGG1 is functional.
Functional studies revealed that cells containing recombinant OGG1 were
more proficient at repairing oxidative damage in their mtDNA, and this
increased repair led to increased cellular survival following
oxidative stress.
Conditional Targeting of the DNA Repair Enzyme hOGG1 into
Mitochondria*
,,,, and¶
Department of Cell Biology and Neuroscience,
College of Medicine, University of South Alabama, Mobile, Alabama 36688 and the § Department of Pediatrics, Wells Center for
Pediatric Research, Indiana University Medical School,
Indianapolis, Indiana 46202
*
This work was supported by National Institutes of Health
Grants ES03456, ES05865, and AG19602 and a Feasibility Grant from the
United States Army.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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