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Abstract
Cellular responses to DNA damage and replication stress are coordinated by an intricate network of repair pathways known as the DNA damage response (DDR). Central to the DDR is the essential kinase ataxia telangiectasia mutated and Rad3-related (ATR), along with its indispensable subunit ATR-interacting protein (ATRIP). Following recruitment and activation, ATR phosphorylates a number of effector proteins, including p53 and CHK1, to initiate DNA repair, cell cycle checkpoints, and replication fork stability. Failure to properly activate such pathways can lead to genome instability, cell death, and development of diseases including cancer. However, the ATR signaling pathway has not yet been established. An incomplete understanding of DDR regulatory mechanisms hinders our ability to effectively diagnose and treat a range of diseases, especially since ATR inhibitors have emerged as promising cancer therapeutics. Here, we found a novel ATRIP binding partner (ABP) which directly binds to ATRIP, and we identified the interaction site in ATRIP. Genetic knockout of ABP in human cells influences the ATR signaling pathway with hydroxyurea and mitomycin C treatment. In vitro ATR and ataxia telangiectasia mutated (ATM) kinase assays show that ABP affects phosphorylation signal in ATR/ATM substrates. Overall, this work begins to define a new regulator of the ATR pathway and sheds light on the synergy between various components of the DDR.