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.

中文翻译：

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FOXP1 磷酸化拮抗其 O-GlcNAcylation 以响应复制应激调节 ATR 激活。


ATR 信号转导对于感应和响应复制应激至关重要;因此，任何缺陷都会损害细胞功能和存活。ATR 本身是通过严格调节的机制激活的。在这里，我们将 FOXP1（一种包含叉头框的转录因子）确定为协调 ATR 激活的调节因子。我们表明，与作为转录因子的作用不同，FOXP1 起支架的作用，直接与 RPA-ssDNA 和 ATR-ATRIP 复合物结合，促进 ATR 的募集和激活。这个过程受 FOXP1 O-GlcNAcylation 调节，FOXP1 O-GlcNAcylation 抑制其与 ATR 的相互作用，而 CHK1 介导的 FOXP1 磷酸化在复制应激下抑制其 O-GlcNAcylation。支持该环的生理相关性，我们发现在各种肿瘤组织中发现了致病性 FOXP1 突变体，这些突变体具有 ATR 激活受损和复制叉稳定性停滞。因此，我们得出结论，FOXP1 可能作为相关肿瘤的潜在化疗靶点。