Understanding BRCA2 Molecule May Lead To Cancer Prevention Strategies

Professor Xiaodong Zhang Professor of Macromolecular Structure and Function Department of Medicine Imperial College, London, UKMedicalResearch.com Interview with:
Professor Xiaodong Zhang
Professor of Macromolecular Structure and Function
Department of Medicine
Imperial College, London, UK


Medical Research: What are the main findings of the study?

Prof. Zhang: Since its discovery 20 years ago, the BRCA2 gene and its protein product, BRCA2, have been under intensive investigations. The importance of the BRCA2 protein lies in the central roles it plays in the most faithful DNA damage repair pathway. Mutations in BRCA2 thus can cause defects in this repair pathway, making the repair inefficient or forcing cells to use alternative repair methods that are prone to mistakes, all of which contribute to mutations in the genomic DNA, thus increase the risk of cancer development. Our study aims to understand how BRCA2 works through studying its 3-dimensional structures and its interactions with other key partners in the repair pathway.

Our study provides first 3-dimensional views of BRCA2 and BRCA2-RAD51 and reveals that BRCA2 molecules exist as pairs and a BRCA2 pair recruit two sets of RAD51 molecules arranged in opposite orientations. Our study also shows a single stranded DNA binds across the BRCA2 dimer and that BRCA2 increases the frequency of RAD51 filament formation events, presumably to increase the efficiency of establishing a longer filament required for searching for matching strands of DNA in intact sister chromatin. Our results thus not only define the precise roles of BRCA2 in helping RAD51 filament formation, but how it helps RAD51 loading onto single stranded DNA.


Medical Research: What was most surprising about the results?

Prof. Zhang: BRCA2, one of the largest proteins in the cell, still works in pairs.

Medical Research: What should clinicians and patients take away from your report?

Prof. Zhang: Through a molecular understanding of its structures and mechanisms, such as how intact BRCA2 protein works in the DNA repair, what is the nature of the cancer predisposition mutations, we could start to develop strategies to correct the defects in BRCA2 to ensure repair could be carried out, thus to prevent cancer development. Alternatively, we could develop ways to hamper repairs in cancer cells, thus to promote cell death.

Medical Research: What recommendations do you have for future research as a result of this study?

Prof. Zhang: Our current research focuses on revealing greater details of the BRCA2 molecule, its interactions with other proteins in the repair pathway as well as its regulation. With increasing knowledge of this protein, how it interacts with and recruits RAD51 precisely and how it is regulated, we will be a step closer to develop therapeutics to protect healthy cells and/or to combat cancer cells.

Citation:

Structure and Mechanism of Action of the BRCA2 Breast Cancer Tumor Suppressor
Taha Shahid, Joanna Soroka, Eric H Kong, Laurent Malivert, Michael J McIlwraith, Tillmann Pape, Stephen C West , Xiaodong Zhang

Nature Structural & Molecular Biology(2014) doi:10.1038/nsmb.28