DNA polymerase delta is required for early mammalian embryogenesis.
BACKGROUND
In eukaryotic cells, DNA polymerase delta (Poldelta), 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 Poldelta in mammalian development has not been thoroughly investigated.


RESULTS
To examine this role, we used a gene targeting strategy to generate two kinds of Pold1 mutant mice: Poldelta-null (Pold1(-/-)) mice and D400A exchanged Poldelta (Pold1(exo/exo)) mice. The D400A exchange caused deficient 3'-5' exonuclease activity in the Poldelta protein. In Poldelta-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 Poldelta 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 delta is essential for mammalian early embryogenesis and that the 3'-5' exonuclease activity of DNA polymerase delta is dispensable for normal development but necessary to suppress tumorigenesis.
Uchimura
Arikuni
A
Graduate School of Frontier Biosciences, Osaka University, Suita, Osaka, Japan. uchimura@fbs.osaka-u.ac.jp
Hidaka
Yuko
Y
Hirabayashi
Takahiro
T
Hirabayashi
Masumi
M
Yagi
Takeshi
T
D000818:Animals; D004258:DNA Polymerase III / Q000502:physiology*; D004261:DNA Replication; D047108:Embryonic Development / Q000235:genetics; D005092:Exonucleases; D005838:Genotype; D051379:Mice; D008817:Mice, Mutant Strains; D009369:Neoplasms / Q000209:etiology
D004258:DNA Polymerase III; D005092:Exonucleases