Function of DNA Polymerase α in a Replication Fork and its Putative Roles in Genomic Stability and Eukaryotic Evolution

Abstract

DNA replication takes place during S phase (Kornberg & Baker, 1992). In eukaryotic cells, DNA replication is performed through the concerned action of plural DNA polymerases with their accessory proteins (Wang, 1991; Hubscher et al., 2002; Burgers, 2009). Eukaryotic cells contain three replicative DNA polymerases, named DNA polymerases ┙, ├, and ┝, mitochondrial DNA polymerase ┛, and at least 12 non-replicative DNA polymerases, named DNA polymerases ┚, ┞, ┟, ┠, ┡, ┢, ┣, ┤, and ┥, terminal deoxynucleotidyl transferase (TdT), and Rev1 (Hubscher et al., 2002; Livneh et al., 2010). DNA replication progresses according to the catalytic activity of three replicative DNA polymerases (pol-) ┙, ├, and ┝, cooperatively (Burgers, 2009). Pol-┙ is necessary for the onset of DNA synthesis, which synthesizes RNA-DNA primer in both leading and lagging strands (Wang, 1991; Hubscher et al., 2002; Burgers, 2009). Pol-├ is probably involved in the synthesis of Okazaki fragment in the lagging strand, and pol-┝ is thought to synthesize long DNA strand in the leading strand (Pavlov et al., 2006a; Pavlov et al., 2006b; Pursell et al., 2007) (Fig. 1). Pol-┙ is the first eukaryotic DNA polymerase ever discovered (Bollum, 1960). Its complex type with DNA primase (pol-┙-primase complex) is the only DNA polymerase that can initiate DNA synthesis de novo. Therefore, pol-┙ is an important enzyme for cell survival (Murakami et al., 1985; Budd & Campbell, 1987; Takada-Takayama et al., 1991). Pol-┙primase complex comprises four subunits, each of which is highly conserved in eukaryotes from yeast to human (Wang, 1991). The function of this ‘classical’ DNA polymerase at DNA replication reaction has been well established. Primase is an RNA polymerase. It is able to synthesize RNA primer, following DNA synthesis by the catalytic subunit of pol-┙. Almost all DNA replication researchers consider its role in DNA replication reaction as a mere ‘initiator’ of DNA chain elongation. Nevertheless, several recent examinations of this ‘classical’ DNA polymerase have revealed its heretofore unknown but important roles in DNA replication. They have revealed a link between DNA replication and other cellular dynamism, in addition to advancing the evolution of eukarya. According to this recent progress, I describe several topics related to eukaryotic pol-┙ in this chapter, not only as an ‘initiator’, but also as a ‘key regulator’.