Estrogen receptor α is a putative substrate for the BRCA1 ubiquitin ligase

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 104; no. 14; pp. 5794 - 5799
• Main Authors: Eakin, Catherine M, MacCoss, Michael J, Finney, Gregory L, Klevit, Rachel E
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 03.04.2007; National Acad Sciences
• Subjects: Amino Acid Sequence; Binding Sites; Biological Sciences; BRCA1 Protein - chemistry; BRCA1 Protein - isolation & purification; BRCA1 Protein - metabolism; Breast cancer; Cell growth; Escherichia coli - genetics; Estrogen Receptor alpha - metabolism; Estrogen receptors; Estrogens; Female; Gene expression regulation; Genetic mutation; Humans; Mass spectroscopy; Models, Molecular; Molecular Sequence Data; Protein Structure, Tertiary; Proteins; Substrate Specificity; Tumor Suppressor Proteins - chemistry; Tumor Suppressor Proteins - metabolism; Ubiquitin-Protein Ligases - chemistry; Ubiquitin-Protein Ligases - metabolism; Ubiquitins
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0610887104

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 α (ERα) transcriptional activation by BRCA1. Here, we show that ERα is a putative substrate for the BRCA1/BARD1 ubiquitin ligase, suggesting a possible mechanism for regulation of ERα activity by BRCA1. Our results show ERα is predominantly monoubiquitinated in a reaction that involves interactions with both BRCA1 and BARD1. The regions of BRCA1/BARD1 necessary for ERα 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 ERα ubiquitination. The identification of ERα as a putative BRCA1/BARD1 ubiquitination substrate reveals a potential link between the loss of BRCA1/BARD1 ligase activity and tissue-specific carcinoma.