Molecular dissection of PrimPol, a novel primase-polymerase involved in damage tolerance during DNA replication in eukaryotic cells

TL;DRAbstract

PrimPol is a recently identified member of the archaeo-eukaryotic primase (AEP) family of proteins. It possesses both primase and polymerase activities and is involved in the replication of both nuclear and mitochondrial DNA. PrimPol is predicted to possess an AEP polymerase and a UL52-like zinc finger domain. This thesis establishes the roles of these domains in the context of PrimPol’s catalytic activities. Although apparently dispensable for polymerase activity, the zinc finger is essential for maintaining primase activity and also appears to play an important role in regulating the processivity and fidelity of PrimPol’s extension activities. A recently study identified a PrimPol mutation (Y89D) that is potentially associated with the development of high myopia in humans. Here, the biochemical defects associated with this mutant are analysed and described. This protein variant has a significant reduction in polymerase activity. Mutational analysis suggests that the hydrophobic r

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