Structural analysis of BRCA1 reveals modification hotspot

Yanping Liang, William J. Dearnaley, A. Cameron Varano, Carly E. Winton, Brian L. Gilmore, Nick A. Alden, Zhi Sheng, Deborah F. Kelly

Research output: Contribution to journalArticle

4 Scopus citations

Abstract

Cancer cells afflicted with mutations in the breast cancer susceptibility protein (BRCA1) often suffer from increased DNA damage and genomic instability. The precise manner in which physical changes to BRCA1 influence its role in DNA maintenance remains unclear. We used single-particle electron microscopy to study the three-dimensional properties of BRCA1 naturally produced in breast cancer cells. Structural studies revealed new information for full-length BRCA1, engaging its nuclear binding partner, the BRCA1-associated RING domain protein (BARD1). Equally important, we identified a region in mutated BRCA1 that was highly susceptible to ubiquitination. We refer to this site as a modification “hotspot.” Ubiquitin adducts in the hotspot region proved to be biochemically reversible. Collectively, we show how key changes to BRCA1 affect its structure-function relationship, and present new insights to potentially modulate mutated BRCA1 in human cancer cells.

Original languageEnglish (US)
Article number1701386
JournalScience Advances
Volume3
Issue number9
DOIs
StatePublished - 2017

All Science Journal Classification (ASJC) codes

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    Liang, Y., Dearnaley, W. J., Cameron Varano, A., Winton, C. E., Gilmore, B. L., Alden, N. A., Sheng, Z., & Kelly, D. F. (2017). Structural analysis of BRCA1 reveals modification hotspot. Science Advances, 3(9), [1701386]. https://doi.org/10.1126/sciadv.1701386