Cells respond to cytotoxic DNA double-strand breaks by recruiting repair proteins to the damaged site. Phosphorylation of the histone variant H2AX at S139 and Y142 modulate its interaction with downstream DNA repair proteins and their recruitment to DNA lesions. Here we report ATM-dependent ZNF506 localization to the lesion through MDC1 following DNA damage. ZNF506， in turn， recruits the protein phosphatase EYA， resulting in dephosphorylation of H2AX at Y142， which further facilitates the recruitment of MDC1 and other downstream repair factors. Thus， ZNF506 regulates the early dynamic signaling in the DNA damage response (DDR) pathway and controls progressive downstream signal amplification. Cells lacking ZNF506 or harboring mutations found in cancer patient samples are more sensitive to radiation， offering a potential new therapeutic option for cancers with mutations in this pathway. Taken together， these results demonstrate how the DDR pathway is orchestrated by ZNF506 to maintain genomic integrity.