Ataxia Telangiectasia and Rad3-related protein (ATR) is an apical kinase of the DNA Damage Response (DDR) pathway responsible for detecting and resolving damaged DNA. Because cancer cells depend heavily on the DNA damage checkpoint for their unchecked proliferation and propagation, ATR has gained enormous popularity as a cancer therapy target in recent decades. Yet, ATR inhibitors have not been the silver bullets as anticipated, with clinical trials demonstrating toxicity and mixed efficacy. To investigate whether the toxicity and mixed efficacy of ATR inhibitors arise from their off-target effects related to ATR’s multiple roles within and outside the DDR pathway, we have analyzed recently published studies on ATR’s non-canonical roles. Recent studies have elucidated that ATR plays a wide role throughout the cell cycle that is separate from its function in the DDR. This includes maintaining nuclear membrane integrity, detecting mechanical forces, and promoting faithful chromosome segregation during mitosis. In this review, we summarize the canonical, DDR-related roles of ATR and also focus on the non-canonical, multifaceted roles of ATR throughout the cell cycle and their clinical relevance. Through this summary, we also address the need for re-assessing clinical strategies targeting ATR as a cancer therapy based on these newly discovered roles for ATR.
共济失调毛细血管扩张症和Rad3相关蛋白（ATR）是DNA损伤应答（DDR）通路中的关键激酶，负责检测和修复受损DNA。由于癌细胞高度依赖DNA损伤检查点来实现其不受控制的增殖和扩散，近几十年来ATR作为癌症治疗靶点备受关注。然而，ATR抑制剂并未如预期般成为"灵丹妙药"，临床试验显示其存在毒性且疗效参差不齐。为探究ATR抑制剂的毒性和疗效差异是否源于其在DDR通路内外多重功能导致的脱靶效应，我们系统分析了近期关于ATR非经典功能的研究。最新研究表明，ATR在整个细胞周期中发挥着独立于DDR功能的广泛作用，包括维持核膜完整性、感知机械力以及促进有丝分裂中染色体的准确分离。本综述不仅总结了ATR经典的DDR相关功能，更着重探讨其在细胞周期中的非经典多面性功能及其临床意义。基于这些新发现的功能，我们进一步提出需要重新评估以ATR为靶点的癌症治疗临床策略。
A TRilogy of ATR’s Non-Canonical Roles Throughout the Cell Cycle and Its Relation to Cancer
肿瘤(癌症)患者之家