Role of Tor1 and Tel1 in repair of oxidative DNA lesions in mitochondrial DNA in yeast

• Grant number: 12/08064-5
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: June 01, 2012
• End date: December 31, 2012
• Field of knowledge: Biological Sciences - Genetics - Molecular Genetics and Genetics of Microorganisms
• Principal Investigator: Nadja Cristhina de Souza Pinto
• Grantee: Mariana Farias de Miranda Paz
• Host Institution: Instituto de Química (IQ). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

When eukaryotic, most of the cellular ATP is formed in mitochondria, by the process of oxidative phosphorylation. However, a side effect of aerobic metabolism is that a small percentage of electrons being transported by the electron transport chain can directly reduce molecular oxygen, generating Reactive Oxygen Species (ROS). These species are highly reactive and can attack biomolecules such as lipids, proteins, and DNA. Mitochondrial DNA is located very near the site of the formation of ROS and therefore is more susceptible to the formation of oxidative damage in both the nitrogenous bases and the deoxyribose. These oxidative modifications, if not properly repaired, can cause mutations and cytotoxicity, leading to various pathological processes (such as cancer) and degenerative (such as aging). DNA oxidative damage is repaired primarily by the base excision repair (BER) pathway, which consists of five sequential reactions catalyzed by 4 enzymes already characterized in the nucleus and mitochondria. On the other hand, it is unclear how the BER pathway is modulated in mitochondria and if the efficiency of this pathway is dependent on the metabolic state of the cell. This project aims to investigate the role of two proteins, Tor1 and Tel 1, in modulating the repair of oxidative lesions in mtDNA, using the yeast Saccharomyces cerevisiae as a biological model. Tel1 protein is homologous to ATM mammal protein, which plays an important role in the cellular response to DNA damage, whereas the Tor1 protein controls the cellular energy metabolism in response to nutrient availability. The results obtained in this project helped better characterize the molecular pathways of repair of oxidative damage to DNA in mitochondria and the understanding of how these pathways are regulated by the bioenergetic state of the cells.(AU)