Mouse PrimPol Outperforms Its Human Counterpart as a Robust DNA Primase

The human PrimPol counteracts DNA replication stress by repriming DNA synthesis when fork progression is hindered by UV light or hydroxyurea treatment, or by encountering complex DNA structures, such as G-quadruplexes, R-loops, or interstrand crosslinks. The <i>Mus musculus</i> PrimPol (<i>Mm</i>PrimPol) shares a high degree of amino acid similarity with its human ortholog; however, as shown here, <i>Mm</i>PrimPol exhibits a more powerful primase activity compared to the human enzyme. Such a robust primase activity relies on an enhanced ability to bind the 5' site nucleotide, and consequently to form initial dimers and further mature primers. Additionally, a shorter linker between the AEP core and the Zn finger domain (ZnFD) in the murine homolog likely promotes a constitutive closing of these domains into a primase-ready configuration. Consequently, a reinforced close configuration of the ZnFD would explain why <i>Mm</i>PrimPol has a more robust primase, but a very limited DNA polymerization on an existing primer.