期刊
NUCLEIC ACIDS RESEARCH
卷 45, 期 8, 页码 4507-4518出版社
OXFORD UNIV PRESS
DOI: 10.1093/nar/gkx084
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资金
- Dutch Technology Foundation (STW) [NWO-nano11425]
- Cancer Genomics Netherlands (NWO gravitation), Marie Curie Reintegration Grant [FP7-276898]
- NanoNextNL, a micro and nanotechnology consortium of the Government of the Netherlands
- Dutch Technology Foundation
The tumor suppressor BRCA2 is a large multifunctional protein mutated in 50-60% of familial breast cancers. BRCA2 interacts with many partners and includes multiple regions with potentially disordered structure. In homology directed DNA repair BRCA2 delivers RAD51 to DNA resulting in removal of RPA and assembly of a RAD51 nucleoprotein filament. Dynamic rearrangements of BRCA2 likely drive this molecular hand-off initiating DNA strand exchange. We show human BRCA2 forms oligomers which can have an extended shape. Scanning force microscopy and quantitative single molecule fluorescence define the variety of BRCA2 complexes, reveal dramatic rearrangements upon RAD51 binding and the loading of RAD51 patches on single strand DNA. At sites of repair in cell nuclei, super-resolution microscopy shows BRCA2 and RAD51 arranged in largely separate locations. We identified dynamic structural transitions in BRCA2 complexes suggested to facilitate loading of RAD51 onto RPA coated single strand DNA and subsequent release of BRCA2.
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