Cyclin D1 Integrates Estrogen-Mediated DNA Damage Repair Signaling

The cyclin D1 gene encodes the regulatory subunit of a holoenyzme that phosphorylates the retinoblastoma protein (pRb) and nuclear respiratory factor (NRF1) proteins. The abundance of cyclin D1 determines estrogen-dependent gene expression in the mammary gland of mice. Using estradiol (E-2) and an E-2-dendrimer conjugate that is excluded from the nucleus, we demonstrate that E-2 delays the DNA damage response (DDR) via an extranuclear mechanism. The E-2-induced DDR required extranuclear cyclin D1, which bound ER alpha at the cytoplasmic membrane and augmented AKT phosphorylation (Ser473) and gamma H2AX foci formation. In the nucleus, E2 inhibited, whereas cyclin D1 enhanced homology-directed DNA repair. Cyclin D1 was recruited to gH2AX foci by E-2 and induced Rad51 expression. Cyclin D1 governs an essential role in the E-2-dependent DNA damage response via a novel extranuclear function. The dissociable cytoplasmic function to delay the E-2-mediated DDR together with the nuclear enhancement of DNA repair uncovers a novel extranuclear function of cyclin D1 that may contribute to the role of E2 in breast tumorigenesis.