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This version published online on May 8, 2007
Molecular Endocrinology, doi:10.1210/me.2006-0519
A more recent version of this article appeared on July 1, 2007
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Submitted on December 4, 2006
Accepted on April 30, 2007

The DNA Repair Protein Flap Endonuclease-1 (FEN-1) Modulates Estrogen-Responsive Gene Expression

Jennifer R. Schultz-Norton, Kjirsten A. Walt, Yvonne S. Ziegler, Ian X. McLeod, John R. Yates, Lori T. Raetzman, and Ann M. Nardulli*

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. and J.R.Y.), The Scripps Institute, LaJolla, California 92037

* To whom correspondence should be addressed. E-mail: anardull{at}life.uiuc.edu.

The ligand-occupied estrogen receptor {alpha} (ER{alpha}) initiates changes in gene expression through its interaction with target DNA. The capacity of ER{alpha} 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{alpha}-mediated transcription, we have isolated and identified proteins associated with ER{alpha} when it is bound to the consensus estrogen response element (ERE). 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{alpha} and enhances the interaction of ER{alpha} with ERE-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. Taken together, our studies help to elucidate the functional consequence of the ER{alpha}-FEN-1 interaction and increase our understanding of the elaborate regulatory mechanisms that drive estrogen-responsive gene expression and DNA repair.
Key words: estrogen receptor {alpha} • transcription • flap endonuclease-1 • DNA repair

NURSA Molecule Pages Link:

Nuclear Receptors:   ERα  |  PR
Ligands:   17β-Estradiol



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