Regulation of Estrogen Receptor Alpha by the SET7 lysine methyltransferase

• Type of Material: Article
• Authors: Krithika Subramanian, Emory University; Da Jia, Emory University; Priya Kapoor, Emory University; Doris R. Powell, Emory University; Robert E. Collins, Emory University; Dipali Sharma, Emory University; Junmin Peng, Emory University; Xiaodong Cheng, Emory University; Paula M. Vertino, Emory University
• Language: English
• Date: 2008-05-09
• Publisher: Elsevier (Cell Press): 12 month embargo
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2008 Elsevier Inc. Published by Elsevier Inc.
• License: Creative Commons Attribution-NonCommerical-NoDerivs 3.0 Unported
• Final Published Version (URL): http://dx.doi.org/10.1016/j.molcel.2008.03.022
• Title of Journal or Parent Work: Molecular Cell
• ISSN: 1097-2765
• Volume: 30
• Issue: 3
• Start Page: 336
• End Page: 347
• Grant/Funding Information: This work was supported in part by National Institutes of Health grants 2RO1 CA077337 (PMV), 2RO1 GM068680 (XC) and P50 AG025688 (JP), an American Cancer Society Research Scholar grant RSG-02-144-01 (PMV), and funds from the Burris Foundation (KS) and the Georgia Research Alliance (XC).
• Research Categories: Biology, Cell; Biology, Molecular

Abstract

Summary Estrogen receptor α (ER) is a ligand-dependent transcription factor. Upon binding estrogen, ER recruits coactivator complexes with histone acetyltransferase or methyltransferase activities to activate downstream target genes. In addition to histones, coactivators can modify ER itself and other proteins in the transactivation complex. Here, we show that ER is directly methylated at lysine 302 (K302) by the SET7 methyltransferase. SET7-mediated methylation stabilizes ER and is necessary for the efficient recruitment of ER to its target genes, and their transactivation. The SET7-ER complex structure reveals the molecular basis for ER peptide recognition and predicts that modifications or mutations of nearby residues would affect K302 methylation. Indeed, a breast cancer-associated mutation at K303 (K303R) alters methylation at K302 in vitro and in vivo. These findings raise the possibility that generation, recognition, and removal of modifications within the ER hinge region generates “ER modification cassettes” that yield distinct patterns for signaling downstream events.