ATRdependent

ATR-dependent refers to cellular processes and responses that require the ATR kinase to function. ATR stands for Ataxia Telangiectasia and Rad3-related protein, a serine/threonine kinase in the PI3K-like kinase (PIKK) family. It acts as a key sensor and mediator of the DNA damage response, with a prominent role in responding to replication stress and accumulation of single-stranded DNA.

Activation of ATR occurs at sites of replication stress when extensive single-stranded DNA is coated by Replication Protein A (RPA). The ATR–ATRIP complex is recruited, and activation is further promoted by factors such as TopBP1 and ETAA1. Once activated, ATR phosphorylates a range of substrates including Chk1, RPA32, BRCA1, and others. This signaling cascade leads to cell cycle checkpoint enforcement and coordinated DNA repair, helping to stabilize replication forks and prevent premature mitosis.

Functions commonly described as ATR-dependent include the S-phase and G2/M checkpoints, fork stabilization, replication stress response, and the coordination of homologous recombination and other repair processes. Through these activities, ATR maintains genome stability and helps cells survive conditions that disrupt DNA replication, such as ultraviolet damage or oncogene-induced replication stress.

Clinical relevance is evident in cancer therapy and genetic disease. Inhibitors of ATR (for example, berzosertib and ceralasertib) are being investigated in clinical trials to enhance the effectiveness of DNA-damaging agents and other therapies. Genetic mutations in ATR are associated with Seckel syndrome, a developmental disorder characterized by microcephaly and growth retardation; loss of BRCA-like ATR signaling can also be lethal in some model organisms, underscoring ATR’s essential role in genome maintenance.

See also: ATR–CHK1 pathway, DNA damage response, replication stress.