Purified human BRCA2 stimulates RAD51-mediated recombination

By R. Jensen, A. Carreira, S. Kowalczykowski. Nature, 2010

684 citations recorded by the source corpus.

Mutation of the breast cancer susceptibility gene, BRCA2, leads to breast and ovarian cancers. Mechanistic insight into the functions of human BRCA2 has been limited by the difficulty of isolating this large protein (3,418 amino acids). Here we report the purification of full-length BRCA2 and show that it both binds RAD51 and potentiates recombinational DNA repair by promoting assembly of RAD51 onto single-stranded DNA (ssDNA). BRCA2 acts by targeting RAD51 to ssDNA over double-stranded DNA, enabling RAD51 to displace replication protein-A (RPA) from ssDNA and stabilizing RAD51–ssDNA filaments by blocking ATP hydrolysis. BRCA2 does not anneal ssDNA complexed with RPA, implying it does not directly function in repair processes that involve ssDNA annealing. Our findings show that BRCA2 is a key mediator of homologous recombination, and they provide a molecular basis for understanding how this DNA repair process is disrupted by BRCA2 mutations, which lead to chromosomal instability and cancer.

Subfields: Genetics, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/a150f8c2e32806ee42441a430784f74be233f0e5

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Citations in the corpus

• Sources of DNA double-strand breaks and models of recombinational DNA repair. (2014, background): “is replaced by orthologs of the mammalian BRCA2 protein (Jensen et al. 2010; Liu et al. 2010; Holloman 2011).”
• Dynamics of DNA damage response proteins at DNA breaks: a focus on protein modifications. (2011, background): “Additionally, HERC2 stabilizes RNF168 protein levels, thereby regulating ubiquitin-dependent re- tention of 53BP1 and BRCA1 at DSB sites (Bekker-Jensen et al. 2010).”
• Homologous recombination and human health: the roles of BRCA1, BRCA2 and associated proteins (2015, background): “…RAD51-mediator function was further confirmed with purified human BRCA2, which specifically promotes RAD51 filament assembly on ssDNA over dsDNA (Jensen et al. 2010; Liu et al. 2010; Thorslund et al. 2010), leading to displacement of RPA to stimulate strand exchange (Jensen et al. 2010; Liu et…”