The role of mitochondrial DNA double-strand break .. (MITODSBR)
The role of mitochondrial DNA double-strand break repair in human disease and normal ageing
Start date: Sep 11, 2012,
End date: Sep 10, 2015
Mitochondrial DNA (mtDNA) deletions accumulate in aged post-mitotic tissue and in individuals with neurodegenerative diseases, leading to local energy defects. Understanding the mechanism of mtDNA deletion formation is an essential step in trying to prevent their occurrence.My hypothesis is that mtDNA deletions occur during mtDNA repair via a double strand break (DSB) repair pathway. I will address the different components of this hypothesis by mechanistic studies of cell lines derived from patients, transgenic cell culture and in vitro biochemistry.This project also aims to identify and characterize novel mtDNA DSB repair factors. We will study candidate mtDSB genes by RNAi and confirm that the proteins are recruited to mtDNA after specific induction of mtDSBs. In a complementary approach we will search for protein interactions partners of the already identified mtDSB repair proteins by immunoprecipitations. Identified proteins will be analyzed in vitro, with the long-term goal to reveal the molecular details of human mtDSB repair.Further we will use patient cell lines and transgenic cell culture to identify new therapeutic pathways that can be used to counteract mtDNA deletion formation in neurodegenerative disease and normal ageing. If we can show as I propose that repair is the mechanism underlying mtDNA deletion formation, increasing levels of antioxidants could prevent the induction of DSBs and mtDNA deletions in neurodegenerative disease.
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