ATRmediated

ATRmediated refers to cellular processes governed by the ATR kinase signaling pathway in response to DNA replication stress and DNA damage. The ATR-ATRIP complex is recruited to sites where single-stranded DNA is coated with RPA, such as stalled replication forks or resected double-strand breaks. Activation is amplified by the ATR activators TopBP1 and ETAA1, leading to phosphorylation of downstream effectors, most notably the checkpoint kinase CHK1. Through CHK1 and other substrates, ATR signaling enforces cell cycle checkpoints and coordinates DNA repair.

Key outcomes of ATR-mediated signaling include stabilization of stalled replication forks, suppression of late origin firing, and promotion of fork restart and repair via homologous recombination and other pathways. ATR also modulates replication timing and helps prevent mitotic catastrophe by delaying entry into mitosis when DNA remains under replicated or damaged. The pathway integrates with other DNA damage response systems, including ATM and DNA-PKcs, to coordinate a comprehensive response.

Genetic disruption of ATR often results in severe defects or lethality in model organisms, and in humans hypomorphic ATR mutations can cause developmental disorders such as Seckel syndrome, with increased sensitivity to replication stress. Because many cancers experience elevated replication stress, ATR inhibitors are being developed to selectively sensitize tumor cells and are studied in combination with DNA-damaging agents or PARP inhibitors. Prominent ATR inhibitors in clinical development include berzosertib and ceralasertib, among others.

Research on ATR-mediated signaling continues to define its spectrum of substrates and its interactions with fork protection factors, chromatin remodelers, and other DDR pathways, underscoring its central role in maintaining genome stability.