53BP1 是一种成熟的 DNA 损伤修复因子，最近出现，可严格调节基因表达，从而抑制肿瘤和神经发育。然而，其确切功能和调控机制仍不清楚。在这里，我们发现 ATM 对 53BP1 丝氨酸 25 的磷酸化是皮质脑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 的动态磷酸化控制着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。从机制上讲，ATM 和 RNF168 控制 53BP1 与基因位点的结合，从而直接影响基因调控，尤其是神经元分化和成熟的基因。 53BP1 丝氨酸 25 磷酸化有效阻止其与二价或 H3K27me3 占据的启动子结合，特别是在调节 H3K4 甲基化、神经元功能和细胞增殖的基因上。除了 53BP1 之外，ATM 依赖性磷酸化还表现出广泛的作用，调节神经元分化、细胞骨架、p53 调节的因素，以及皮质类器官分化过程中的关键信号通路（如 ATM、BDNF 和 WNT）。总之，我们的数据表明，53BP1 和 ATM 之间的相互作用协调了细胞形态发生、组织组织和对人类皮质发育至关重要的发育途径的基本遗传程序。版权所有：© 2024 Lim 等人。这是一篇根据知识共享署名许可条款分发的开放获取文章，允许在任何媒体上不受限制地使用、分发和复制，前提是注明原始作者和来源。

53BP1 is a well-established DNA damage repair factor that has recently emerged to critically regulate gene expression for tumor suppression and neural development. However, its precise function and regulatory mechanisms remain unclear. Here, we showed that phosphorylation of 53BP1 at serine 25 by ATM is required for neural progenitor cell proliferation and neuronal differentiation in cortical brain organoids. Dynamic phosphorylation of 53BP1-serine 25 controls 53BP1 target genes governing neuronal differentiation and function, cellular response to stress, and apoptosis. Mechanistically, ATM and RNF168 govern 53BP1's binding to gene loci to directly affect gene regulation, especially at genes for neuronal differentiation and maturation. 53BP1 serine 25 phosphorylation effectively impedes its binding to bivalent or H3K27me3-occupied promoters, especially at genes regulating H3K4 methylation, neuronal functions, and cell proliferation. Beyond 53BP1, ATM-dependent phosphorylation displays wide-ranging effects, regulating factors in neuronal differentiation, cytoskeleton, p53 regulation, as well as key signaling pathways such as ATM, BDNF, and WNT during cortical organoid differentiation. Together, our data suggest that the interplay between 53BP1 and ATM orchestrates essential genetic programs for cell morphogenesis, tissue organization, and developmental pathways crucial for human cortical development.Copyright: © 2024 Lim et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.