DNA polymerase α-primase can function as a translesion DNA polymerase

Replication of cellular chromosomes requires a primase to generate short RNA primers to initiate genomic replication. While bacterial and archaeal primase generate short RNA primers, the eukaryotic primase, Pol-primase, contains both RNA primase and DNA polymerase (Pol) subunits that function together to form a >20 base hybrid RNA-DNA primer. Interestingly, the DNA Pol1 subunit of Pol lacks a 3-5 proofreading exonuclease, contrary to the high fidelity normally associated with DNA replication. However, Polo and Pol{delta} synthesize the majority of the eukaryotic genome and both contain 3-5 exonuclease activity for high fidelity. None the less, even the small amount of DNA produced by Pol1 in each of the many RNA/DNA primers during chromosome replication adds up to tens of millions of nucleotides in a human genome. Thus it has been a longstanding question why Pol1 lacks a proofreading exonuclease. We show here that Pol is uniquely capable of traversing common oxidized or hydrolyzed template nucleotides and propose that Pol evolved to bypass these common template lesions when they are encountered during chromosome replication. Significance statementEukaryotic Pol-primase contains DNA polymerase (Pol1) and RNA primase subunits that together synthesize a >20 nucleotide hybrid RNA-DNA primer. Bacteria and archaea only require a dozen or less RNA residues to prime DNA synthesis. Therefore, why do eukaryotes require the additional DNA? We propose, and demonstrate here that Pol1, which lacks a proofreading 3-5 exonuclease, is capable of traversing some common template lesions produced in the normal hydrolytic and metabolic oxidative environment of cells. Thus, we hypothesize that Pol1 activity within the eukaryotic primase evolved to help replisomes bypass template damage. Bypassed damaged sites can be dealt with by repair processes after replication has occurred.