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Structural and mechanistic studies of the breast cancer tumour suppressor BRCA2 in DNA double strand break repair

Xiaodong Zhang

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Medical Research Council (MRC)
Since its discovery, the breast cancer tumor suppressor brca2 gene and the 3418 amino acid protein it encodes (BRCA2) have been the subject of intense study. BRCA2 plays important roles in homologous recombination, the main mechanism in error-free homology directed DNA double strand repair during the S and G2 phases. Human BRCA2 is one of the largest proteins in the cell. The large size and low abundance of BRCA2 made it extremely challenging to purify the full length protein, which has hindered its biochemical, structural and mechanistic characterization. However, very recently, three groups including that of Dr. Stephen West, have reported the purification and biochemical characterization of BRCA2, creating an exciting opportunity for structural studies. In this proposed research, we will employ biochemistry expertise in Dr. Stephen West's laboratory and electron microscopy single particle analysis technique in Prof. Xiaodong Zhang's laboratory in combination with protein homology modeling and algorithms development in Dr. Paul Bates group for fitting crystal structures into low resolution EM reconstructions. Together we will characterize the structures of BRCA2 alone and its complexes with RAD51 and PALB2 in order to provide a molecular basis for its roles in DNA double-strand break repair. The information obtained will not only provide us with the first glimpse of the structures of this important protein and its interacting partners, but also reveal insights into how BRCA2 helps to load RAD51 onto single stranded DNA that eventually leads to strand invasion and homologous recombination. This will constitute a significant step towards our understanding of this key cellular process that has a direct link to cancer and aging. It will improve our knowledge about the cause of the disease and also offer opportunities for novel therapeutic approaches for DNA damage repair mechanisms .

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