BRCA1 & Cancer

Rachel E. Klevit

Edmond H. Fischer/WRF Professor of Biochemistry

University of Washington, Seattle, WA 98195

The first gene to be associated with hereditary high risk for breast cancer, BRCA1, was discovered in 1994. More than twenty years later, the only known biochemical function of BRCA1 is its Ubiquitin E3 ligase activity. The ligase activity arises from a small domain (~100 residues of the 1893 total) known as a “RING” and inherited missense mutations in RING residues are among the most frequent and penetrant in BRCA1 families. Our long journey to understand the function of BRCA1 and the consequences of its loss of function began with NMR studies to determine the solution structure of the active BRCA1 ligase complex. We have continued to turn to NMR with its rich toolbox of experiments throughout our quest to find a molecular explanation for why mutations in BRCA1, and its sister protein, BARD1, are so intimately linked to high risk for breast and ovarian cancer.

Biosketch

Prof. Rachel Klevit has a B.A. in Chemistry from Reed College. She obtained her doctorate from Oxford University where she applied (one-dimensional) NMR spectroscopy to study the conformational properties of the recently discovered protein, calmodulin. Following post-doctoral studies at Duke University, she was drawn to the University of Washington where the first 500 MHz NMR spectrometer in the US had just been installed. There, she applied the newly developed two-dimensional NMR approaches to determine one of the first de novo protein structures, for a bacterial phosphotransfer protein, HPr. She joined the Dept. of Biochemistry faculty at the University of Washington where she has spent her entire faculty career. Her lab uses NMR, biochemistry, and many assorted biophysical techniques to address questions of protein recognition, especially via weak and transient interactions. Current interests include fundamental mechanisms of protein ubiquitylation, small heat shock proteins, and intrinsically disordered transcriptional activators. The work of Prof. Klevit and her team has been recognized by numerous awards, including Margaret Oakley Dayhoff award, DuPont Young Investigator award, Fritz Lippmann award, and the Dorothy Crowfoot Hodgkins award.

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