Decreased PARP-1 levels accelerate embryonic lethality but attenuate neuronal apoptosis in DNA polymerase beta-deficient mice.
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.
Sugo
Noriyuki
N
Kihara Institute for Biological Research and Graduate School of Integrated Science, Yokohama City University, 641-12 Maioka-cho, Totsuka-ku, Yokohama 244-0813, Japan.
Niimi
Naoko
N
Aratani
Yasuaki
Y
Masutani
Mitsuko
M
Suzuki
Hiroshi
H
Koyama
Hideki
H
D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology*; D019951:DNA Polymerase beta / Q000172:deficiency* / Q000502:physiology; D004622:Embryo, Mammalian / Q000002:abnormalities / Q000166:cytology* / Q000378:metabolism; D005260:Female; D051379:Mice; D018345:Mice, Knockout; D009153:Mutagens / Q000494:pharmacology / Q000633:toxicity; D009154:Mutation; D009420:Nervous System / Q000196:embryology / Q000378:metabolism* / Q000473:pathology; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism* / Q000502:physiology; D012694:Serine / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
D009153:Mutagens; D016159:Tumor Suppressor Protein p53; D012694:Serine; C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D019951:DNA Polymerase beta