Role of TFAM in modulation of DNA pol gamma activity by p53

• Grant number: 18/07700-1
• Support type: Scholarships in Brazil - Post-Doctorate
• Effective date (Start): October 01, 2018
• Effective date (End): April 30, 2019
• Field of knowledge: Biological Sciences - Genetics - Mutagenesis
• Principal Investigator: Nadja Cristhina de Souza Pinto
• Grantee: Mahdi Hajimohammadi
• Home Institution: Instituto de Química (IQ). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated research grant: 17/04372-0 - Mitochondrial DNA: mechanisms for genome integrity maintenance and impact on disease, AP.TEM

Abstract

Mitochondria play several and essential roles in mammalian cells. They are the main cellular site of ATP generation and participate directly in controlling cell fate after injury. Mitochondrial function depends on the integrity of the oxidative phosphorylation system, whose complexes contain subunits encoded by both the nuclear and the mitochondrial DNA (mtDNA). Thus, maintaining the integrity of the mtDNA is essential for mitochondrial function. However, the mtDNA sits at the inner side of the inner mitochondrial membrane, where reactive oxygen species are generated, as byproducts of the electron transport chain. In fact, the mtDNA accumulates oxidative damage and shows elevated mutagenesis when compared with nuclear DNA. As mitochondria contain an efficient base excision repair mechanism, on possible explanation for this would be that the mtDNA is more accessible for damage formation. Although lacking histone, the mtDNA is packed in a nucleoproteic complex known as nucleoid, for which the mitochondrial transcription factor A (TFAM) is the main protein component. TFAM binds to mtDNA, and we have recently shown that it delays mtDNA repair by restricting access to DNA repair enzymes. On the other hand, p53 modulates TFAM binding to mtDNA, facilitating access to DNA repair enzymes. We have also shown that p53 interacts functionally with DNA pol gamma, the mains repair/replication polymerase in mitochondria. Thus, we propose to investigate whether TFAM/p53/pol gamma constitute a functional complex regulating access of DNA repair activities to sites of damage in the mitochondrial DNA when cytosolic p53 is translocated to mitochondrial matrix in response to stress conditions.