Phosphorylation of 53BP1 by ATM enforce neurodevelopmental programs in cortical organoids.
Phosphorylation of 53BP1 by ATM enforce neurodevelopmental programs in cortical organoids.
复制标题
ATM 对 53BP1 的磷酸化增强了皮质类器官的神经发育程序。
DOI：
10.1101/2023.05.04.539457
复制
发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Peng,Ju
中科院分区：
文献类型：
--
作者：
Lim,Bitna;Djekidel,MohamedNadhir;Matsui,Yurika;Jung,Seunghyun;Yuan,Zuo-Fei;Wang,Xusheng;Yang,Xiaoyang;Pilehroud,AbbasShirinifard;Pan,Haitao;Wang,Fang;Pruett-Miller,Shondra;Kavdia,Kanisha;Pagala,Vishwajeeth;Fan,Yiping;Peng,Ju
53BP1 是一种成熟的 DNA 损伤修复因子，最近被证明可以调节基因表达并严重影响肿瘤抑制和神经发育。对于基因调控，53BP1是如何调控的仍不清楚。在这里，我们表明 ATM 的 53BP1-丝氨酸 25 磷酸化是皮质类器官中神经祖细胞增殖和神经元分化所必需的。 53BP1-丝氨酸 25 磷酸化动力学控制神经元分化和功能、细胞对应激的反应和细胞凋亡的 53BP1 靶基因。除了 53BP1 之外，ATM 还需要神经元分化、细胞骨架、p53 调节以及皮质类器官分化的 ATM、BNDF 和 WNT 信号通路中的因子磷酸化。总体而言，我们的数据表明 53BP1 和 ATM 控制人类皮质发育所需的关键遗传程序。
53BP1 is a well-established DNA damage repair factor recently shown to regulate gene expression and critically influence tumor suppression and neural development. For gene regulation, how 53BP1 is regulated remains unclear. Here, we showed that 53BP1-serine 25 phosphorylation by ATM is required for neural progenitor cell proliferation and neuronal differentiation in cortical organoids. 53BP1-serine 25 phosphorylation dynamics controls 53BP1 target genes for neuronal differentiation and function, cellular response to stress, and apoptosis. Beyond 53BP1, ATM is required for phosphorylation of factors in neuronal differentiation, cytoskeleton, p53 regulation, and ATM, BNDF, and WNT signaling pathways for cortical organoid differentiation. Overall, our data suggest that 53BP1 and ATM control key genetic programs required for human cortical development.