Two Forms of Human DNA Polymerase Delta: Who Does What and Why?
Biochemistry and Molecular Biology
DNA polymerase delta (Pol delta) plays a central role in lagging strand DNA synthesis in eukaryotic cells, as well as an important role in DNA repair processes. Human Pol delta4 is a heterotetramer of four subunits, the smallest of which is p12. Pol delta3 is a trimeric form that is generated in vivo by the degradation of the p12 subunit in response to DNA damage, and during entry into S-phase. The biochemical properties of the two forms of Pol delta, as well as the changes in their distribution during the cell cycle, are reviewed from the perspective of understanding their respective cellular functions. Biochemical and cellular studies support a role for Pol delta3 in gap filling during DNA repair, and in Okazaki fragment synthesis during DNA replication. Recent studies of cells in which p12 expression is ablated, and are therefore null for Pol delta4, show that Pol delta4 is not required for cell viability. These cells have a defect in homologous recombination, revealing a specific role for Pol delta4 that cannot be performed by Pol delta3. Pol delta4 activity is required for D-loop displacement synthesis in HR. The reasons why Pol delta4 but not Pol delta3 can perform this function are discussed, as well as the question of whether helicase action is needed for efficient D-loop displacement synthesis. Pol delta4 is largely present in the G1 and G2/M phases of the cell cycle and is low in S phase. This is discussed in relation to the availability of Pol delta4 as an additional layer of regulation for HR activity during cell cycle progression.
Lee, M. Y., Zhang, S., Wang, X., Chao, H., Zhao, H., Darzynkiewicz, Z., Zhang, Z., & Lee, E. (2019). Two Forms of Human DNA Polymerase Delta: Who Does What and Why?. DNA Repair, 102656. https://doi.org/10.1016/j.dnarep.2019.102656