Neonatal lethality with abnormal neurogenesis in mice deficient in DNA polymerase beta

Abstract

DNA polymerase β (Polβ) has been implicated in base excision repair in mammalian cells. However, the physiological significance of this enzyme in the body remains unclear. Here, we demonstrate that mice carrying a targeted disruption of the Polβ gene showed growth retardation and died of a respiratory failure immediately after the birth. Histological examination of the embryos revealed defective neurogenesis characterized by apoptotic cell death in the developing central and peripheral nervous systems. Extensive cell death occurred in newly generated post-mitotic neuronal cells and was closely associated with the period between onset and cessation of neurogenesis. These findings indicate that Polβ plays an essential role in neural development.

The dark side of a tumor suppressor: anti-apoptotic p53

“…Induction of BER clearly contributes to apoptosis resistance and deficiencies in crucial components of this pathway such as apurinic/apyrimidinic endonuclease-1/redox factor-1 (APE, Ref-1) or DNA polymerase b (polb) cause a p53-dependent pre-and postnatal lethality, respectively, and lead to hypersensitivity toward certain types of DNA-damaging agents. 53,54 Consistent with this, upregulation of either APE/Ref-1, polb or 8-oxoguanine-DNA glycosylase (OGG1), another enzyme of the BER machinery, is often observed in various cancers and correlates with apoptosis resistance. 51,52 Although p53 does not transcriptionally control expression of any member of this pathway, it markedly stimulates BER activity in vitro and in vivo in a cell cycle-specific manner and this effect was suggested to be due to its ability to directly interact with APE/ Ref-1, OGG1 and polb.…”

Early steps in the DNA base excision/single-strand interruption repair pathway in mammalian cells

“…Efforts to generate cell lines from APE1 null embryos were also uniformly unsuccessful which distinguishes it from Polb. Null mutation for Polb in mice is also embryonic lethal (although the embryos survived longer) [118]. However, Polb null mouse embryonic fibroblast lines could be established which have normal viability [119].…”

DNA polymerase beta null mouse embryonic fibroblasts harbor a homozygous null mutation in DNA polymerase iota

“…Characterization of the pol β knockout mouse [29,30] [34,54,55]; among other studies too numerous to mention herein. The most definitive and reproducible endpoint that has been used to evaluate pol β *To whom correspondence should be addressed: Robert W. Sobol, Hillman Cancer Center, University of Pittsburgh Cancer Institute, Research Pavilion, Suite 2.6, 5117 Centre Avenue, Pittsburgh, PA 15213-1863, Phone: 412-623-7764, Fax: 412-623-7761, e-mail: rws9@pitt.edu.…”

“…Several groups reported complete BER in vitro with pol β and additional purified proteins [22,23,25]. Although it was demonstrated in heterologous systems (E. coli and Saccharomyces cerevisiae) that pol β can conduct DNA replication and repair in vivo [26,27], it was not until a mouse gene knockout was made that the specificity of the repair conducted by pol β was defined [28].Characterization of the pol β knockout mouse [29,30] [34,54,55]; among other studies too numerous to mention herein. The most definitive and reproducible endpoint that has been used to evaluate pol β *To whom correspondence should be addressed: Robert W. Sobol, Hillman Cancer Center, University of Pittsburgh Cancer Institute, Research Pavilion, Suite 2.6, 5117 Centre Avenue, Pittsburgh, PA 15213-1863, Phone: 412-623-7764, Fax: 412-623-7761, e-mail: rws9@pitt.edu.…”