Interaction of the Double-Strand Break Repair Kinase DNA-PK and Estrogen Receptor-α

Estrogens are suggested to play a role in the development and progression of proliferative diseases such as breast cancer. Like other steroid hormone receptors, the estrogen receptor-alpha (ER alpha) is a substrate of protein kinases, and phosphorylation has profound effects on its function and activity. Given the importance of DNA-dependent protein kinase (DNA-PK) for DNA repair, cell cycle progression, and survival, we hypothesized that it modulates ER alpha signaling. Here we show that, upon estrogen stimulation, DNA-PK forms a complex with ER alpha in a breast cancer cell line (MELN). DNA-PK phosphorylates ER alpha at Ser-118. Phosphorylation resulted in stabilization of ER alpha protein as inhibition of DNA-PK resulted in its proteasomal degradation. Activation of DNA-PK by double-strand breaks or its inhibition by siRNA technology demonstrated that estrogen-induced ER alpha activation and cell cycle progression is, at least, partially dependent on DNA-PK.