Grant: Project Grant

There is a critical unmet need to prevent and cure cancer, with one of the major chemotherapeutic approaches being treatment with chemicals that block nuclear DNA replication and cell division, leading the nuclear DNA breaks and death of the cancer. However, while these chemicals have profound effects on the cancer and have been used clinically for over 30 years, they are limited by the toxicity that has been difficult to overcome. This proposal focuses on a new, and very unexpected discovery into the mechanisms by which these drugs promote nuclear DNA breakage and cell death. We show that the mitochondria, long known as the energy powerhouse of the cell, play a critical role in the induction of nuclear DNA damage, whether caused by addition of the chemotherapeutic drugs, or in other pathways like inflammation and mitochondrial metabolic stress. Mitochondria have their own DNA, called mtDNA, in hundreds of copies per cell that are remnants of their a-proteobacterial origin. Our data suggest that when mtDNA replication becomes stalled the circular DNA is extruded out of the mitochondria within vesicles. We show that mtDNA, and the machinery that drives the formation of mitochondrial derived vesicles, are essential for the generation of nuclear DNA breaks. However, we do not understand the details of how the mtDNA can signal to activate the destruction of DNA in the nucleus. This proposal states a series of hypothesis based on our preliminary data and previous work to map this pathway at the cellular level. In dissecting this new mitochondria-to-nuclear signaling axis we hope to identify new therapeutic targets to block toxicity and nuclear DNA damage in multiple contexts.