Mutations in mitochondrial DNA (mtDNA) cause a number of human diseases such as MELAS (mitochondrial encephalopathy lactic acidosis and stroke) and LHON (Leber's hereditary optic neuropathy) and may contribute to the pathogenesis of other more common diseases, including Parkinson's disease and diabetes. These mutations reflect an inadequacy of mtDNA repair processes and indicate that more detailed understanding of DNA repair processes in mitochondria is required. Recent studies have shown that some types of damage, mainly those amenable to base excision repair, can be repaired in mtDNA. The base excision repair pathway handles abasic sites in mtDNA produced by spontaneous base loss or by any of several damage-specific glycosylases. Some nuclear genes for glycosylases involved in repair of oxidative DNA damage provide enzyme to both the nucleus and to mitochondria. Our laboratory has recently reconstituted a complete pathway for base excision repair of mtDNA with proteins purified from mitochondria. We propose experiments to characterize mitochondrial glycosylases that act on 3- methyl adenine residues in order to test the hypothesis that mitochondrial contain a variant of the cellular alkyl adenine glycosylase. This enzyme may also process endogenous damage generated by reaction of lipid peroxidation products with mtDNA. Abasic site repair requires an enzyme to cleave abasic sites, AP (apurinic/apyrimidinic) endonuclease. We also propose a series of experiments to characterize the mitochondrial AP endonuclease. Finally, we propose to apply our expertise in mtDNA repair to investigate the mechanism whereby an environmental toxin known to cause Parkinson's disease interferes with the initiation of mtDNA replication. We will test the hypothesis that this inhibition results from the sequestration of DNA polymerase gamma at sites of DNA damage.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Program Projects (P01)
Project #
2P01ES004068-14
Application #
6301318
Study Section
Project Start
2000-04-10
Project End
2001-03-31
Budget Start
Budget End
Support Year
14
Fiscal Year
2000
Total Cost
$218,986
Indirect Cost
Name
State University New York Stony Brook
Department
Type
DUNS #
804878247
City
Stony Brook
State
NY
Country
United States
Zip Code
11794
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