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).
Highlights
polymerase δ (Pol δ) plays a central role, together with Pol ε and Pol α/primase, as the DNA polymerases that synthesize the daughter DNA strands at the eukaryotic replication fork
polymerase delta interaction protein 46 (PDIP46) was revealed to be a remarkably potent activator of Pol δ4 in the synthesis of the 7 kb M13 DNA, with an apparent Kd of ca. 34 nM [56]. The mechanisms for this activation could be due to several causes. These include an increase in processivity, possibly because PDIP46 may stabilize Pol δ binding to proliferating cell nuclear antigen (PCNA) by a bridging interaction, as well as by a direct activation that involves alteration of the kinetic properties of Pol δ4
In addition to a general role as a leading strand polymerase, Pol δ4/PDIP46 could act in an analogous way as proposed above (Figure 6) in lagging strand synthesis
Summary
Pol δ plays a central role, together with Pol ε and Pol α/primase, as the DNA polymerases that synthesize the daughter DNA strands at the eukaryotic replication fork. The unraveling of the biochemistry of the mammalian DNA polymerases has posed significant experimental challenges. Knowledge of the enzymology of the DNA polymerases is essential to an understanding of their cellular functions. The biochemical approach is critical as pointed out by Arthur Kornberg in the context of the discovery and unraveling of the processes of prokaryotic DNA replication [1]. We have focused on the regulation of Pol δ by modification of its subunit structure, and the modulation of its functions by accessory proteins. For a broader view of regulation of Pol δ and other polymerases, see [2,3]
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