Functions, Regulation, and Therapeutic Implications of the ATR Checkpoint Pathway.
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.
Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, Massachusetts 02129; email: zou.lee@mgh.harvard.edu.
Stephanie A
SA
Yazinski
Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, Massachusetts 02129; email: zou.lee@mgh.harvard.edu.|Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02115.
Lee
L
Zou
D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics / Q000378:metabolism*; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair; D004261:DNA Replication; D042822:Genomic Instability; D006801:Humans; D053858:Metabolic Networks and Pathways; D058990:Molecular Targeted Therapy / Q000379:methods; D009369:Neoplasms / Q000235:genetics*
C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins
ATR; Chk1; DNA damage; DNA repair; cancer therapy; checkpoint; genomic instability; replication stress