The evolutionary landscape of modern-day replicases and archaeo-eukaryotic primases may have giant viral interventions.

The viruses from the phylum Nucleocytoviricota have been a central part of the investigation to understand the evolution of viruses because of their atypically large particle size and large DNA genome encoding ORFs for protein translation, metabolism, and DNA replication and repair. Acanthamoeba polyphaga mimivirus (APMV), the founding member of the phylum, encodes a DNA-repair multifunctional PrimPol enzyme belonging to the archaeo-eukaryotic primase (AEP) superfamily. AEPs are enzymes present in all domains of life forms and viruses, and their versatile nature has been hypothesized to have aided in genomic replication and repair during evolution. The broad substrate specificity of AEPs allows them to act as primase, polymerase, and translesion synthesis polymerase (TLS). This multi-operational mode makes them a potential candidate for a primordial enzyme that could have been a part of the still inefficient ancient replication machinery. In this article, using the available sequence, biochemical, and structural information of AEPs, we explore the potential origins of modern-day replicases. In this context, we propose that AEPs, specifically PrimPols, have been central to the inception of modern-day replication machinery. Using APMV PrimPol as a representative candidate, we propose a model in which the parallel evolution of naked DNA elements, early viruses, cellular organisms, and the replication machinery might have occurred.