Integrity of mitochondrial DNA is vital to functions of the organelle that include supply energy to sustain cellular activities, cell division and programmed cell death. Mutations on mitochondrial DNA are associated with neurodegenerative disorders, such as Parkinson's and Huntington's diseases, cardiovascular and skeletal muscular disorders. The high concentration of reactive oxygen species in mitochondria causes abundant oxidative damage on DNA. DNA damage repair is chiefly repaired by the base excision repair pathway. Although a wealth of knowledge on nuclear DNA base excision repair exists, comparatively much less is known about mitochondrial DNA repair. We propose to study the structures and functions of a central component in human mitochondrial DNA repair pathway, DNA polymerase gamma (Pol ?), and its interaction with another critical component, mitochondrial exonuclease ExoG. The proposed studies combine structural biology, solution biophysics, enzyme kinetics as well as chemical synthesis aiming to provide a comprehensive view of mitochondrial base excision repair.
Despite the fact that oxidative mitochondrial DNA damage has been connected to a number of health issues: cancers, premature aging, as well as, cardiovascular, skeletal muscular and neurological disorders, little is known about two of the three subpathways in which the body attempts to repair this damage. This project focuses on these two lesser known subpathways with the goal of revealing the basis for mitochondrial DNA oxidative damage repair.
