NEIL1 and NEIL2 DNA glycosylases protect neural crest development against mitochondrial oxidative stress
NEIL1 and NEIL2 DNA glycosylases protect neural crest development against mitochondrial oxidative stress
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DOI：
10.7554/elife.49044
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发表时间：
2019-09-30
期刊：
影响因子：
7.7
通讯作者：
Niehrs, Christof
中科院分区：
文献类型：
--
作者：
Han, Dandan;Schomacher, Lars;Niehrs, Christof
碱基切除修复（BER）不仅在维持基因组的完整性，而且在主动DNA去甲基化和表观遗传基因调控中发挥作用。这种双重作用提出了一个问题，即BER因子缺乏引起的表型异常是否是由于DNA损伤或DNA去甲基化受损。在这里，我们研究了双功能DNA糖基化酶/裂解酶NEIL 1和NEIL 2，它们在氧化损伤的修复和表观遗传去甲基化中起作用。非洲爪蟾胚胎和分化中的小鼠胚胎干细胞（mESC）中的Neil-deficiency导致颅神经嵴细胞（cNCC）发育的令人惊讶的限制缺陷。Neil-deficiency elevates氧化应激诱导的TP 53依赖性DNA损伤反应，这损害了早期cNCC的规范。Tdg缺陷型mESCs的上位性实验显示表观遗传DNA去甲基化没有参与。相反，Neil缺陷导致线粒体DNA特异性氧化损伤，这引发TP 53介导的内在凋亡。因此，NEIL 1和NEIL 2 DNA糖基化酶在神经嵴分化期间保护线粒体DNA免受氧化损伤。
Base excision repair (BER) functions not only in the maintenance of genomic integrity but also in active DNA demethylation and epigenetic gene regulation. This dual role raises the question if phenotypic abnormalities resulting from deficiency of BER factors are due to DNA damage or impaired DNA demethylation. Here we investigate the bifunctional DNA glycosylases/lyases NEIL1 and NEIL2, which act in repair of oxidative lesions and in epigenetic demethylation. Neil-deficiency in Xenopus embryos and differentiating mouse embryonic stem cells (mESCs) leads to a surprisingly restricted defect in cranial neural crest cell (cNCC) development. Neil-deficiency elicits an oxidative stress-induced TP53-dependent DNA damage response, which impairs early cNCC specification. Epistasis experiments with Tdg-deficient mESCs show no involvement of epigenetic DNA demethylation. Instead, Neil-deficiency results in oxidative damage specific to mitochondrial DNA, which triggers a TP53-mediated intrinsic apoptosis. Thus, NEIL1 and NEIL2 DNA glycosylases protect mitochondrial DNA against oxidative damage during neural crest differentiation.