Genetic interaction between DNA polymerase β and DNA-PKcs in embryogenesis and neurogenesis
Genetic interaction between DNA polymerase β and DNA-PKcs in embryogenesis and neurogenesis
复制标题
DOI：
10.1038/sj.cdd.4401543
复制
发表时间：
2005-02
影响因子：
12.4
通讯作者：
N. Niimi;N. Sugo;Y. Aratani;H. Koyama
中科院分区：
文献类型：
--
作者：
N. Niimi;N. Sugo;Y. Aratani;H. Koyama
DNA聚合酶β（Polβ）参与碱基切除修复。Polβ基因敲除小鼠在有丝分裂后的神经元细胞中表现出凋亡，并在出生时死亡。此外，小鼠缺乏非同源末端连接（NHEJ），DNA双链断裂修复的主要途径，导致大量的神经元凋亡。严重联合免疫缺陷（SCID）小鼠在编码DNA依赖性蛋白激酶催化亚基（DNA-PKcs）（NHEJ的组成部分）的基因中存在突变，并表现出淋巴细胞生成缺陷。为了研究Polβ和DNA-PKcs之间的相互作用，我们产生Polβ和DNA-PKcs双重缺陷的小鼠。与Pol β −/−和DNA-PKcs scid/scid胚胎相比，Polβ −/− DNA-PKcs scid/scid胚胎表现出更大的发育延迟、更广泛的神经元凋亡和更早的致死性。此外，为了研究p53在表型中的参与，我们产生了Polβ−/− DNA-PKcs scid/scid p53−/−三突变小鼠。突变体没有表现出细胞凋亡，但在妊娠中期有缺陷的神经形成是致命的。这些结果表明Polβ和DNA-PKcs在胚胎发生和神经发生中存在遗传相互作用。
DNA polymerase β (Polβ) has been implicated in base excision repair. Polβ knockout mice exhibit apoptosis in postmitotic neuronal cells and die at birth. Also, mice deficient in nonhomologous end-joining (NHEJ), a major pathway for DNA double-strand break repair, cause massive neuronal apoptosis. Severe combined immunodeficiency (SCID) mice have a mutation in the gene encoding DNA-dependent protein kinase catalytic subunit (DNA-PKcs), the component of NHEJ, and exhibit defective lymphogenesis. To study the interaction between Polβ and DNA-PKcs, we generated mice doubly deficient in Polβ and DNA-PKcs. Polβ−/− DNA-PKcs scid/scid embryos displayed greater developmental delay, more extensive neuronal apoptosis, and earlier lethality than Polβ−/− and DNA-PKcs scid/scid embryos. Furthermore, to study the involvement of p53 in the phenotype, we generated Polβ−/− DNA-PKcs scid/scid p53−/− triple-mutant mice. The mutants did not exhibit apoptosis but were lethal with defective neurulation at midgestation. These results suggest a genetic interaction between Polβ and DNA-PKcs in embryogenesis and neurogenesis.