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The Deoxyribonucleic Acid Repair Protein Flap Endonuclease-1 Modulates Estrogen-Responsive Gene Expression

Department of Molecular and Integrative Physiology (J.R.S.-N., K.A.W., Y.S.Z., L.T.R., A.M.N.), University of Illinois, Urbana, Illinois 61801; and Department of Cell Biology (I.X.M., J.R.Y.), The Scripps Institute, La Jolla, California 92037

Address all correspondence and requests for reprints to: Ann M. Nardulli, Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, 524 Burrill Hall, 407 South Goodwin Avenue, Urbana, Illinois 61801. E-mail: anardull{at}life.uiuc.edu.

The ligand-occupied estrogen receptor (ER) initiates changes in gene expression through its interaction with target DNA. The capacity of ER to modulate gene expression is influenced by the association of the receptor with a variety of coregulatory proteins. To further understand the role of these coregulatory proteins in ER-mediated transcription, we have isolated and identified proteins associated with ER when it is bound to the consensus estrogen response element. One of the proteins identified in this complex, flap endonuclease-1 (FEN-1), is required for DNA replication and repair. We show that FEN-1 interacts directly with ER and enhances the interaction of ER with estrogen response element-containing DNA. More importantly, chromatin immunoprecipitation and RNA interference assays demonstrate that endogenously expressed FEN-1 associates with the native pS2 gene in MCF-7 cells and influences estrogen-responsive gene expression. Interestingly, estrogen differentially regulates expression of FEN-1 in mouse uterine epithelial, stromal, and myometrial cells. Together, our studies help to elucidate the functional consequence of the ER-FEN-1 interaction and increase our understanding of the elaborate regulatory mechanisms that drive estrogen-responsive gene expression and DNA repair.

NURSA Molecule Pages Link:

Nuclear Receptors:   ERα  |  PR

Ligands:   17β-Estradiol

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