Apurinic endonuclease-1 preserves neural genome integrity to maintain homeostasis and thermoregulation and prevent brain tumors
Apurinic endonuclease-1 preserves neural genome integrity to maintain homeostasis and thermoregulation and prevent brain tumors
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DOI：
10.1073/pnas.1809682115
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发表时间：
2018-12-26
影响因子：
11.1
通讯作者：
McKinnon, Peter J.
中科院分区：
文献类型：
--
作者：
Dumitrache, Lavinia C.;Shimada, Mikio;McKinnon, Peter J.
神经基因组的频繁氧化修饰是神经系统高氧消耗的副产品。快速纠正氧化DNA损伤是必不可少的，因为基因组稳定性是神经稳态的重要决定因素。无嘌呤/无嘧啶内切酶1 （APE1，也称为“APEX1”或“REF1”）是修复DNA氧化损伤的关键酶，尽管该酶在神经系统发育和维持中的具体作用在很大程度上尚不清楚。在这里，利用小鼠Ape1的条件失活，我们确定了该蛋白在出生后选择性地在大脑中发挥的关键作用，与组织氧合从胎盘供应转向呼吸供应相一致。虽然在整个神经发生过程中缺乏APE1的小鼠在出生时几乎没有明显的表型，但在出生后立即观察到与DNA损伤相关的快速而明显的全脑退行性变化，导致早期死亡。出乎意料的是，Ape1（Nes-cre）小鼠出现体温过低，伴有持续颤抖，这与体温调节血清素能神经元的丧失有关。我们发现APE1对fos1诱导的海马即时早期基因表达的选择性调控至关重要。最后，APE1的缺失和p53的失活导致脑肿瘤的易感性，包括髓母细胞瘤和胶质母细胞瘤，暗示氧化DNA损伤是这些疾病的病因。我们的研究揭示了APE1是有害氧化DNA损伤的主要抑制因子，并揭示了出生后神经系统呼吸氧合的特异性和广泛的致病后果。
Frequent oxidative modification of the neural genome is a by-product of the high oxygen consumption of the nervous system. Rapid correction of oxidative DNA lesions is essential, as genome stability is a paramount determinant of neural homeostasis. Apurinic/apyrimidinic endonuclease 1 (APE1; also known as "APEX1" or "REF1") is a key enzyme for the repair of oxidative DNA damage, although the specific role(s) for this enzyme in the development and maintenance of the nervous system is largely unknown. Here, using conditional inactivation of murine Ape1, we identify critical roles for this protein in the brain selectively after birth, coinciding with tissue oxygenation shifting from a placental supply to respiration. While mice lacking APE1 throughout neurogenesis were viable with little discernible phenotype at birth, rapid and pronounced brain-wide degenerative changes associated with DNA damage were observed immediately after birth leading to early death. Unexpectedly, Ape1(Nes-cre) mice appeared hypothermic with persistent shivering associated with the loss of thermoregulatory serotonergic neurons. We found that APE1 is critical for the selective regulation of Fos1-induced hippocampal immediate early gene expression. Finally, loss of APE1 in combination with p53 inactivation resulted in a profound susceptibility to brain tumors, including medulloblastoma and glioblastoma, implicating oxidative DNA lesions as an etiologic agent in these diseases. Our study reveals APE1 as a major suppressor of deleterious oxidative DNA damage and uncovers specific and broad pathogenic consequences of respiratory oxygenation in the postnatal nervous system.