Mitochondrial genome replication
In mammalian cells, the mitochondrial genome (mtDNA) encodes only 13 protein subunits of the respiratory chain and the functional RNAs for their translation. As such, the vast majority of proteins required for mitochondrial function and regulation are encoded in the nucleus, including all components of the mtDNA nucleoid - the protein-DNA structure that is the unit of mtDNA inheritance. Thus, the regulation of mtDNA replication and maintenance must rely on anterograde and retrograde signaling communication between mitochondria and other cellular compartments. A minimal mtDNA replisome has been described, comprised of the polymerase gamma (POLG1/POLG2), helicase (Twinkle) and single-stranded DNA binding protein (MTSSB). However, the mechanisms that determine which of the 100s-1000s of nucleoids in each cell are licensed to replicate and when, i.e. the factors that determine the spatiotemporal regulation of mtDNA maintenance, are not understood. Ultimately, I hope to elucidate the molecular basis of mtDNA replication licensing in human cells, which could open up new strategies for the development of therapeutics for metabolic and neurodegenerative disease.
Lewis SC, Joers P, Willcox S, Griffith JD, Jacobs HT, Hyman BC. (2015) A rolling-circle replication mechanism produces multimeric lariats of mitochondrial DNA in Caenorhabditis elegans. PLoS Genetics, 11(2): e1004985.
Joers P, Lewis SC, Fukuoh A, Parhiala M, Ellila S, Holt IJ, Jacobs HT. (2013) Mitochondrial transcription terminator family members mTTF and mTerf5 have opposing roles in coordination of mtDNA synthesis. PLoS Genetics 9(9): e1003800.