Here, we demonstrate that ATM is the PIKK that phosphorylates Hsp90α in response to ionizing radiation (IR) at T5/7 residues in head and neck squamous cell carcinoma cells, lung cancer cells, lung fibroblasts, ATM knockdown and reconstituted cells and mouse embryonic fibroblasts (MEF). Here, HSP90AA1 is linked to head and neck squamous cell carcinoma.