DNA replication in all forms of life relies upon the initiation of synthesis on a single strand template by formation of a short oligonucleotide primer, which is subsequently elongated by DNA polymerases. Two structurally distinct classes of enzymes have evolved to perform this function, namely the bacterial DnaG-type primases and the Archaeal and Eukaryotic primases (AEP). Structural and mechanistic insights have provided a clear understanding of the role of the different domains of these enzymes in the context of the replisome and recent work sheds light upon primase-substrate interactions. We herein review the emerging picture of the primase mechanism on the basis of the structural knowledge obtained to date and propose future directions of this essential aspect of DNA replication.
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