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, E2 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.
Authors' Affiliations: Departments of Cancer Biology and Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania; and.
Zhiping
Z
Li
Authors' Affiliations: Departments of Cancer Biology and Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania; and.
Ke
K
Chen
Authors' Affiliations: Departments of Cancer Biology and Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania; and.
Xuanmao
X
Jiao
Authors' Affiliations: Departments of Cancer Biology and Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania; and.
Chenguang
C
Wang
Authors' Affiliations: Departments of Cancer Biology and Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania; and.
Nicole E
NE
Willmarth
Authors' Affiliations: Departments of Cancer Biology and Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania; and.
Mathew C
MC
Casimiro
Authors' Affiliations: Departments of Cancer Biology and Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania; and.
Weihua
W
Li
Authors' Affiliations: Departments of Cancer Biology and Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania; and.
Xiaoming
X
Ju
Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois.
Sung Hoon
SH
Kim
Stem Cell Biology and Regenerative Medicine, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania; and.
Michael P
MP
Lisanti
Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois.
John A
JA
Katzenellenbogen
Authors' Affiliations: Departments of Cancer Biology and Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania; and director@kimmelcancercenter.org.
Richard G
RG
Pestell
D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002843:Chromatin / Q000378:metabolism; D019938:Cyclin D1 / Q000235:genetics* / Q000378:metabolism; D004249:DNA Damage; D004260:DNA Repair; D004958:Estradiol / Q000378:metabolism; D047628:Estrogen Receptor alpha / Q000378:metabolism; D004967:Estrogens / Q000378:metabolism*; D005260:Female; D006801:Humans; D051379:Mice; D011485:Protein Binding; D034622:RNA Interference; D051135:Rad51 Recombinase / Q000378:metabolism; D015398:Signal Transduction
D002843:Chromatin; D047628:Estrogen Receptor alpha; D004967:Estrogens; D019938:Cyclin D1; D004958:Estradiol; D051135:Rad51 Recombinase