Functions, Regulation, and Therapeutic Implications of the ATR Checkpoint Pathway

Abstract

The ATR (ATM and rad3-related) pathway is crucial for proliferation, responding to DNA replication stress and DNA damage. This critical signaling pathway is carefully orchestrated through a multistep process requiring initial priming of ATR prior to damage, recruitment of ATR to DNA damage lesions, activation of ATR signaling, and, finally, modulation of ATR activity through a variety of post-translational modifications. Following activation, ATR functions in several vital cellular processes, including suppression of replication origin firing, promotion of deoxynucleotide synthesis and replication fork restart, prevention of double-stranded DNA break formation, and avoidance of replication catastrophe and mitotic catastrophe. In many cancers, tumor cells have increased dependence on ATR signaling for survival, making ATR a promising target for cancer therapy. Tumor cells compromised in DNA repair pathways or DNA damage checkpoints, cells reliant on homologous recombination, and cells with increased replication stress are particularly sensitive to ATR inhibition. Understanding ATR signaling and modulation is essential to unraveling which tumors have increased dependence on ATR signaling as well as how the ATR pathway can best be exploited for targeted cancer therapy.

Arabidopsis replication factor C4 is critical for DNA replication during the mitotic cell cycle

“…It was reported that cell cycle blocks provide sufficient time for damage repair (van Vugt and Yaffe, ); only after all DNA defects have been repaired will the cell cycle start again. It is known that ataxia telangiectasia‐mutated protein (ATM) primarily responds to DSBs, while ataxia telangiectasia and Rad3 related protein (ATR) responds to DNA damage and replication fork stall (Awasthi et al ., ; Yazinski and Zou, ). The decrease in transcripts of ATM and ATR indicates that the DNA repair pathway might be inhibited in rfc4‐1 /– FDA seedlings.…”

The DNA damage response pathway in normal hematopoiesis and malignancies

“…ATR is mainly involved in the response to singlestranded DNA breaks (SSBs) that arise from stalled replication forks in S phase or as intermediates of repair DNA lesions. Through its association with the ATR interacting protein (ATRIP), ATR is recruited at sites of RPAcoated SSBs and undergoes autophosphorylation, an essential step for full activation of ATR, mediated by the interaction with TopBP1, Rad17, and 9-1-1 complexes [13]. Active ATR phosphorylates several substrates, including the effector kinase Chk1, activating it.…”

“…Active Chk1 phosphorylates Cdc25A phosphatase and Treslin, which enforce the G2 and S phase arrest and suppression of new origin firing. Additional phosphorylation targets of ATR include RPA, WRN, and MCMs which act locally at stalled replication forks, while others such as FANCI and polη participate in DNA repair [13].…”

A mitosis-specific and R loop–driven ATR pathway promotes faithful chromosome segregation

“…ATR is a master checkpoint kinase safeguarding the genome (1). Loss of ATR during DNA replication increases genomic instability in S phase and subsequent mitosis (2–4).…”