p53 deficiency rescues neuronal apoptosis but not differentiation in DNA polymerase β-deficient mice
p53 deficiency rescues neuronal apoptosis but not differentiation in DNA polymerase β-deficient mice
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DOI：
10.1128/mcb.24.21.9470-9477.2004
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发表时间：
2004-11-01
影响因子：
5.3
通讯作者：
Koyama, H
中科院分区：
文献类型：
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作者：
Sugo, N;Niimi, N;Koyama, H
在哺乳动物细胞中，DNA聚合酶β（Polbeta）在碱基切除修复中起作用。我们先前已经表明，Polbeta缺陷小鼠在发育中的神经系统中表现出广泛的神经元细胞死亡（凋亡），并且小鼠在出生后立即死亡。在这里，我们研究了p53在表型中的潜在作用，p53与DNA损伤传感、细胞周期阻滞和细胞凋亡有关。我们产生了Polbeta（-/-）p53（-/-）双突变小鼠，发现p53缺陷显著地挽救了与Polbeta缺陷相关的神经元凋亡，表明p53介导了神经系统中的凋亡过程。重要的是，Polbeta（-/-）p53（-/-）小鼠神经元祖细胞的增殖和早期分化似乎正常，但它们的大脑明显显示出细胞结构异常;此外，这些小鼠与Polbeta（-/-）p53（+/+）小鼠一样，出生后未能存活。因此，我们强烈建议Polbeta在特定的神经元细胞类型的分化中起着至关重要的作用。
In mammalian cells, DNA polymerase beta (Polbeta) functions in base excision repair. We have previously shown that Polbeta-deficient mice exhibit extensive neuronal cell death (apoptosis) in the developing nervous system and that the mice die immediately after birth. Here, we studied potential roles in the phenotype for p53, which has been implicated in DNA damage sensing, cell cycle arrest, and apoptosis. We generated Polbeta(-/-)p53(-/-) double-mutant mice and found that p53 deficiency dramatically rescued neuronal apoptosis associated with Polbeta deficiency, indicating that p53 mediates the apoptotic process in the nervous system. Importantly, proliferation and early differentiation of neuronal progenitors in Polbeta(-/-) p53(-/-) mice appeared normal, but their brains obviously displayed cytoarchitectural abnormalities; moreover, the mice, like Polbeta(-/-) p53(+/+) mice, failed to survive after birth. Thus, we strongly suggest a crucial role for Polbeta in the differentiation of specific neuronal cell types.