In mammalian cells, DNA polymerase beta (Pol beta) and poly(ADP-ribose) polymerase-1 (PARP-1) have been implicated in base excision repair (BER) and single-strand break repair. Pol beta knockout mice exhibit extensive neuronal apoptosis during neurogenesis and die immediately after birth, while PARP-I knockout mice are viable and display hypersensitivity to genotoxic agents and genomic instability. Although accumulating biochemical data show functional interactions between Pol beta and PARP-1, such interactions in the whole animal have not yet been explored. To study this, we generate Pol beta(-/-)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-I heterozygous mice in a Pol beta 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 Pol beta and PARP-1 play important roles in embryonic development and neurogenesis. (c) 2007 Elsevier Inc. All rights reserved.