Regulation and Modulation of Human DNA Polymerase δ Activity and Function

Abstract

This review focuses on the regulation and modulation of human DNA polymerase δ (Pol δ). The emphasis is on the mechanisms that regulate the activity and properties of Pol δ in DNA repair and replication. The areas covered are the degradation of the p12 subunit of Pol δ, which converts it from a heterotetramer (Pol δ4) to a heterotrimer (Pol δ3), 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 δ4 and Pol δ3 that provide insights into their functions in DNA replication and repair. The second focus of the review involves the functions of two Pol δ 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 δ4, 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 δ3 and Pol δ4 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).

Keywords: DNA damage response; DNA polymerase δ; DNA replication; E3 ligases; PDIP38; PDIP46; Poldip2; Poldip3; cell cycle; enzyme regulation; p12 subunit.

Figure 1

Relative specific activities and proliferating cell nuclear antigen PCNA binding (nM) of Pol δ and its subassemblies. Data from [51].

Figure 2

Overview of the regulation of human Pol δ by degradation of the p12 subunit and the formation of Pol δ3.

Figure 3

Changes in the kinetic constants of Pol δ3 and Pol δ4. The changes are shown as the ratios of the values for Pol δ3/Pol δ4.

Figure 4

Domain map of PDIP46/SKAR.

Figure 5

PDIP46 activates the extension of primers across regions of secondary structure in the template (shown in red).

Figure 6

Pol δ3 and Pol δ4/PDIP46 in lagging strand synthesis. Template regions of secondary structure (red) that pose impediments to Pol δ3 leads to dissociation and triggers a polymerase switch to Pol δ4/PDIP46.

Figure 7

Pol δ4/PDIP46 in leading strand synthesis. Regions of secondary structure that pose impediments to Pol ε (red) lead to disengagement of the catalytic domain of Pol ε. This triggers a polymerase switch to Pol δ4/PDIP46.