Multiple Forms of Human DNA Polymerase Delta Sub-Assembling in Cellular DNA Transactions

Among three major replicative DNA polymerases of the B-family, Pol alpha, Pol delta and Pol epsilon, Pol delta plays an essential role in chromosomal DNA replication and is also involved in various DNA repair processes in eukaryotes. Human Pol delta is commonly viewed as a heterotetrameric complex, consisting of the catalytic subunit p125 and second subunit p50, together with two additional accessory subunits, p68 and p12. A growing body of research has shown that the latter subunits play a critical role in the regulation of Pol delta functions. The formation of a new form of Pol delta, heterotrimer Pol delta 3, is found by virtue of the depletion of p12 through the ubiquitin-proteasome pathway in response to DNA damages that are trigged by UV irradiation, alkylating agents, oxidative and replication stresses. Pol delta 3 exhibits significant differences in properties to its progenitor with a major impact on cellular processes in genomic surveillance, DNA replication and DNA repair. Our recent studies indicate that there exists an alternative pathway for Pol delta 3 formation by calpain-mediated proteolysis of p12 in a calcium-triggered apoptosis in living cells. In this article, we review and discuss the recent advances from our group and others in the studies of human Pol delta with an emphasis on the generation of its multiple forms by reconstitution and subsequent alternations in enzymatic properties, the multiple pathways of the Pol delta 3 formation in living cells, and the phylogenetic analysis of the evolutionary history on POLD4 gene that is for the p12 subunit.