Defects in mitochondrial DNA replication are linked to a wide spectrum of mitochondrial disorders and human diseases. In this study, a team led by Dr. Hanna Yuan discovered that a human mitochondrial protein, ExoG, has the unique activity of cleaving at the junction between RNA and DNA to remove the residual RNA primers from a RNA/DNA hybrid duplex during mitochondrial DNA replication. The team report the crystal structures of ExoG in complex with three different types of nucleic acids, together with biochemical and mutational data, to show the working mechanism of how ExoG preferentially cleaves an RNA-DNA chimeric hybrid duplex.
Their studies provide solid lines of evidence showing that ExoG participates in mitochondrial DNA replication and reveal a previously unrecognized mechanism for the mysterious RNA primer removal process. These findings advance our understanding of DNA replication at the molecular level and set the stage for the discovery of ExoG-dependent processes in organelles and various mitochondrial diseases. The work has been published in Nucleic Acids Research.