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 (E₂) and an E₂-dendrimer conjugate that is excluded from the nucleus, we demonstrate that E₂ delays the DNA damage response (DDR) via an extranuclear mechanism. The E₂-induced DDR required extranuclear cyclin D1, which bound ERα at the cytoplasmic membrane and augmented AKT phosphorylation (Ser473) and γH2AX foci formation. In the nucleus, E ₂ inhibited, whereas cyclin D1 enhanced homology-directed DNA repair. Cyclin D1 was recruited to γH2AX foci by E₂ and induced Rad51 expression. Cyclin D1 governs an essential role in the E₂-dependent DNA damage response via a novel extranuclear function. The dissociable cytoplasmic function to delay the E₂-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.