A TRilogy of ATR's Non-Canonical Roles Throughout the Cell Cycle and Its Relation to Cancer.

Simple Summary: In this review, we introduce and summarize the canonical roles of Ataxia Telangiectasia and Rad3-related protein (ATR) in the DNA damage response (DDR) pathway. More importantly, we also summarize the most recent discoveries of ATR's non-canonical roles in regulating nuclear membrane integrity, mechanical force, chromosome segregation, and its role in PML bodies and discuss how they are relevant to the current progress of ATR inhibitors in clinical trials. 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. [ABSTRACT FROM AUTHOR]