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Ubiquitination and Proteasome-Mediated Degradation of BRCA1 and BARD1 during Steroidogenesis in Human Ovarian Granulosa Cells

State Key Laboratory of Genetic Engineering (Y.L., D.R.), Institute of Genetics, School of Life Sciences, Fudan University, Shanghai 200433, China; Institute for Cancer Genetics (R.B.), Department of Pathology, Columbia University, New York, New York 10032; and Department of Biochemistry and Molecular Genetics (A.A., J.S., X.J., S.D.M., R.L., Y.H.), School of Medicine, University of Virginia, Charlottesville, Virginia 22908

Address all correspondence and requests for reprints to: Rong Li or Yangfen Hu, Department of Molecular Medicine, Institute of Biotechnology, 15355 Lambda Drive, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78245. E-mail: lir3{at}uthscsa.edu (R.L.) or huy3{at}uthscsa.edu (Y.H.).

Germ-line mutations in BRCA1 predispose women to early-onset, familial breast and ovarian cancers. However, BRCA1 expression is not restricted to breast and ovarian epithelial cells. For example, ovarian BRCA1 expression is enriched in ovarian granulosa cells, which are responsible for ovarian estrogen production in premenopausal women. Furthermore, recent tissue culture and animal studies suggest a functional role of BRCA1 in ovarian granulosa cells. Although levels of BRCA1 are known to fluctuate significantly during folliculogenesis and steroidogenesis, the mechanism by which BRCA1 expression is regulated in granulosa cells remains to be elucidated. Here we show that the ubiquitin-proteasome degradation pathway plays a significant role in the coordinated protein stability of BRCA1 and its partner BARD1 in ovarian granulosa cells. Our work identifies the amino-terminal RING domain-containing region of BRCA1 as the degron sequence that is both necessary and sufficient for polyubiquitination and proteasome-mediated protein degradation. Interestingly, mutations in the RING domain that abolish the ubiquitin E3 ligase activity of BRCA1 do not affect its own ubiquitination or degradation in ovarian granulosa cells. The proteasome-mediated degradation of BRCA1 and BARD1 also occurs during the cAMP-dependent steroidogenic process. Thus, the dynamic changes of BRCA1/BARD1 protein stability in ovarian granulosa cells provide an excellent paradigm for investigating the regulation of this protein complex under physiological conditions.

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Coregulators:   BRCA1

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