Regulation and Modulation of Human DNA Polymerase δ Activity and Function

This review focuses on the regulation and modulation of human DNA polymerase delta (Pol delta). The emphasis is on the mechanisms that regulate the activity and properties of Pol delta in DNA repair and replication. The areas covered are the degradation of the p12 subunit of Pol delta, which converts it from a heterotetramer (Pol delta 4) to a heterotrimer (Pol delta 3), in response to DNA damage and also during the cell cycle. The biochemical mechanisms that lead to degradation of p12 are reviewed, as well as the properties of Pol delta 4 and Pol delta 3 that provide insights into their functions in DNA replication and repair. The second focus of the review involves the functions of two Pol delta binding proteins, polymerase delta interaction protein 46 (PDIP46) and polymerase delta interaction protein 38 (PDIP38), both of which are multi-functional proteins. PDIP46 is a novel activator of Pol delta 4, and the impact of this function is discussed in relation to its potential roles in DNA replication. Several new models for the roles of Pol delta 3 and Pol delta 4 in leading and lagging strand DNA synthesis that integrate a role for PDIP46 are presented. PDIP38 has multiple cellular localizations including the mitochondria, the spliceosomes and the nucleus. It has been implicated in a number of cellular functions, including the regulation of specialized DNA polymerases, mitosis, the DNA damage response, mouse double minute 2 homolog (Mdm2) alternative splicing and the regulation of the NADPH oxidase 4 (Nox4).