Decreased PARP-1 levels accelerate embryonic lethality but attenuate neuronal apoptosis in DNA polymerase beta-deficient mice

Biochem Biophys Res Commun. 2007 Mar 16;354(3):656-61. doi: 10.1016/j.bbrc.2006.12.230. Epub 2007 Jan 11.


In mammalian cells, DNA polymerase beta (Polbeta) and poly(ADP-ribose) polymerase-1 (PARP-1) have been implicated in base excision repair (BER) and single-strand break repair. Polbeta knockout mice exhibit extensive neuronal apoptosis during neurogenesis and die immediately after birth, while PARP-1 knockout mice are viable and display hypersensitivity to genotoxic agents and genomic instability. Although accumulating biochemical data show functional interactions between Polbeta and PARP-1, such interactions in the whole animal have not yet been explored. To study this, we generate Polbeta(-/-)PARP-1(-/-) double mutant mice. Here, we show that the double mutant mice exhibit a profound developmental delay and embryonic lethality at mid-gestation. Importantly, the degree of the neuronal apoptosis was dramatically reduced in PARP-1 heterozygous mice in a Polbeta null background. The reduction was well correlated with decreased levels of p53 phosphorylation at serine-18, suggesting that the apoptosis depends on the p53-mediated apoptosis pathway that is positively regulated by PARP-1. These results indicate that functional interactions between Polbeta and PARP-1 play important roles in embryonic development and neurogenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / genetics
  • Apoptosis / physiology*
  • DNA Polymerase beta / deficiency*
  • DNA Polymerase beta / physiology
  • Embryo, Mammalian / abnormalities
  • Embryo, Mammalian / cytology*
  • Embryo, Mammalian / metabolism
  • Female
  • Mice
  • Mice, Knockout
  • Mutagens / pharmacology
  • Mutagens / toxicity
  • Mutation
  • Nervous System / embryology
  • Nervous System / metabolism*
  • Nervous System / pathology
  • Poly (ADP-Ribose) Polymerase-1
  • Poly(ADP-ribose) Polymerases / metabolism*
  • Poly(ADP-ribose) Polymerases / physiology
  • Serine / genetics
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism


  • Mutagens
  • Tumor Suppressor Protein p53
  • Serine
  • Parp1 protein, mouse
  • Poly (ADP-Ribose) Polymerase-1
  • Poly(ADP-ribose) Polymerases
  • DNA Polymerase beta