ETAA1 (ETAA1 activator of ATR kinase) is a replication stress response protein that functions as a critical regulator of ATR kinase activation. ETAA1 accumulates at DNA damage sites through direct interaction with the RPA complex via conserved RPA-binding domains, where it is recruited to stalled replication forks 1. Once localized, ETAA1 directly stimulates ATR kinase activity independently of the TOPBP1 pathway through its ATR-activating domain (AAD), which contains conserved coiled-coil and tryptophan-containing motifs required for ATR binding 2. Dimerization of ETAA1 enhances its ATR-activating potential and is important for optimal signaling 3. ETAA1 regulates distinct ATR targets compared to TOPBP1, with a dominant function during mitosis where it promotes Aurora B kinase activity, chromosome 2, and spindle assembly checkpoint control 4. The ETAA1-ATR pathway becomes essential when DNA replication fidelity is compromised, preventing mitotic chromosome 2 through phosphorylation-dependent control of its AAD 5. Clinically, rare protein-coding variants in ETAA1 associate with ovarian aging phenotypes 6, and ETAA1 functions within the ATR-ATRIP complex to promote DNA damage responses that suppress tumor development 7.