Zhu Xuefei, Gao Congwen, Peng Bin, Xue Jingwei, Xia Donghui, Yang Liu, Zhang Jiexiang, Gao Xinrui, Hu Yilin, Lin Shixian, Gong Peng, Xu Xingzhi
Carson International Cancer Center & Department of General Surgery & Institute of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Shenzhen University General Hospital, Shenzhen University Medical School, 518060, Shenzhen, Guangdong, China.
Guangdong Key Laboratory for Genome Stability & Disease Prevention and Marshall Laboratory of Biomedical Engineering, Shenzhen University Medical School, 518060, Shenzhen, Guangdong, China.
EMBO J. 2025 Jan;44(2):457-483. doi: 10.1038/s44318-024-00323-x. Epub 2024 Dec 2.
ATR signaling is essential in sensing and responding to the replication stress; as such, any defects can impair cellular function and survival. ATR itself is activated via tightly regulated mechanisms. Here, we identify FOXP1, a forkhead-box-containing transcription factor, as a regulator coordinating ATR activation. We show that, unlike its role as a transcription factor, FOXP1 functions as a scaffold and directly binds to RPA-ssDNA and ATR-ATRIP complexes, facilitating the recruitment and activation of ATR. This process is regulated by FOXP1 O-GlcNAcylation, which represses its interaction with ATR, while CHK1-mediated phosphorylation of FOXP1 inhibits its O-GlcNAcylation upon replication stress. Supporting the physiological relevance of this loop, we find pathogenic FOXP1 mutants identified in various tumor tissues with compromised ATR activation and stalled replication fork stability. We thus conclude that FOXP1 may serve as a potential chemotherapeutic target in related tumors.
ATR信号传导在感知和应对复制应激中至关重要；因此，任何缺陷都可能损害细胞功能和存活。ATR自身通过严格调控的机制被激活。在这里，我们鉴定出FOXP1，一种含叉头框的转录因子，作为协调ATR激活的调节因子。我们表明，与它作为转录因子的作用不同，FOXP1作为一种支架发挥作用，并直接结合RPA-ssDNA和ATR-ATRIP复合物，促进ATR的募集和激活。这个过程受FOXP1的O-连接N-乙酰葡糖胺化调控，它抑制FOXP1与ATR的相互作用，而CHK1介导的FOXP1磷酸化在复制应激时抑制其O-连接N-乙酰葡糖胺化。支持这个循环的生理相关性，我们在各种肿瘤组织中发现了具有受损的ATR激活和停滞的复制叉稳定性的致病性FOXP1突变体。因此，我们得出结论，FOXP1可能作为相关肿瘤的潜在化疗靶点。
