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PNAS 104 (14): 5794-5799

Copyright © 2007 by the National Academy of Sciences.


Estrogen receptor {alpha} is a putative substrate for the BRCA1 ubiquitin ligase

Catherine M. Eakin{dagger}, Michael J. MacCoss{ddagger}, Gregory L. Finney{ddagger}, and Rachel E. Klevit{dagger},§

Departments of {dagger}Biochemistry and {ddagger}Genome Sciences, University of Washington, Seattle, WA 98195

Edited by Mary-Claire King, University of Washington, Seattle, WA, and approved February 9, 2007

Received for publication December 7, 2006.

Abstract: The breast cancer suppressor protein, BRCA1, is a ubiquitin ligase expressed in a wide range of tissues. However, inheritance of a single BRCA1 mutation significantly increases a woman's lifetime chance of developing tissue-specific cancers in the breast and ovaries. Recently, studies have suggested this tissue specificity may be linked to inhibition of estrogen receptor {alpha} (ER{alpha}) transcriptional activation by BRCA1. Here, we show that ER{alpha} is a putative substrate for the BRCA1/BARD1 ubiquitin ligase, suggesting a possible mechanism for regulation of ER{alpha} activity by BRCA1. Our results show ER{alpha} is predominantly monoubiquitinated in a reaction that involves interactions with both BRCA1 and BARD1. The regions of BRCA1/BARD1 necessary for ER{alpha} ubiquitination include the RING domains and at least 241 and 170 residues of BRCA1 and BARD1, respectively. Cancer-predisposing mutations in BRCA1 are observed to abrogate ER{alpha} ubiquitination. The identification of ER{alpha} as a putative BRCA1/BARD1 ubiquitination substrate reveals a potential link between the loss of BRCA1/BARD1 ligase activity and tissue-specific carcinoma.

Key Words: breast cancer • ubiquitylation • ubiquitination • steroid hormone receptor

Author contributions: C.M.E. and R.E.K. designed research; C.M.E. performed research; C.M.E., M.J.M., and G.L.F. contributed new reagents/analytic tools; C.M.E. and M.J.M. analyzed data; and C.M.E. and R.E.K. wrote the paper.

The authors declare no conflict of interest.

This article is a PNAS Direct Submission.

This article contains supporting information online at

§To whom correspondence should be addressed. E-mail: klevit{at}

© 2007 by The National Academy of Sciences of the USA

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