Mayle, R.; Georgescu, R.; O'Donnell, M. E.

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 alpha-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 alpha lacks a proofreading exonuclease, contrary to the high fidelity normally associated with DNA replication. However, Pol delta and Pol epsilon synthesize the majority of the eukaryotic genome and both contain proofreading 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 alpha is uniquely capable of traversing common oxidized or hydrolyzed template nucleotides and propose that Pol alpha evolved to bypass these common template lesions when they are encountered during chromosome replication.