DNA Polymerase δ Is Required for Early Mammalian Embryogenesis

BACKGROUND: In eukaryotic cells, DNA polymerase δ (Polδ), whose catalytic subunit p125 is encoded in the Pold1 gene, plays a central role in chromosomal DNA replication, repair, and recombination. However, the physiological role of the Polδ in mammalian development has not been thoroughly investigated. METHODOLOGY/PRINCIPAL FINDINGS: To examine this role, we used a gene targeting strategy to generate two kinds of Pold1 mutant mice: Polδ-null (Pold1 (−/−)) mice and D400A exchanged Polδ (Pold1 (exo/exo)) mice. The D400A exchange caused deficient 3′–5′ exonuclease activity in the Polδ protein. In Polδ-null mice, heterozygous mice developed normally despite a reduction in Pold1 protein quantity. In contrast, homozygous Pold1 (−/−) mice suffered from peri-implantation lethality. Although Pold1 (−/−) blastocysts appeared normal, their in vitro culture showed defects in outgrowth proliferation and DNA synthesis and frequent spontaneous apoptosis, indicating Polδ participates in DNA replication during mouse embryogenesis. In Pold1 (exo/exo) mice, although heterozygous Pold1 (exo/+) mice were normal and healthy, Pold1 (exo/exo) and Pold1 (exo/−) mice suffered from tumorigenesis. CONCLUSIONS: These results clearly demonstrate that DNA polymerase δ is essential for mammalian early embryogenesis and that the 3′–5′ exonuclease activity of DNA polymerase δ is dispensable for normal development but necessary to suppress tumorigenesis.