Models for ATR activation. (A) ATR is primarily activated by TOPBP1 in response to replication stress leading to phosphorylation of hundreds of proteins. ETAA1 contributes to ATR activation in response to replication stress, but regulates a smaller fraction of ATR substrates. (B) ETAA1 activates ATR localized to centromeric regions promoting full Aurora B activity, correct chromosome alignment, and a fully functional SAC.