title: A second DNA binding site in human BRCA2 promotes homologous recombination.
abstract: BRCA2 tumour-suppressor protein is well known for its role in DNA repair by homologous recombination (HR); assisting the loading of RAD51 recombinase at DNA double-strand breaks. This function is executed by the C-terminal DNA binding domain (CTD) which binds single-stranded (ss)DNA, and the BRC repeats, which bind RAD51 and modulate its assembly onto ssDNA. Paradoxically, analysis of cells resistant to DNA damaging agents missing the CTD restore HR proficiency, suggesting another domain may take over its function. Here, we identify a region in the N terminus of BRCA2 that exhibits DNA binding activity (NTD) and provide evidence for NTD promoting RAD51-mediated HR. A missense variant detected in breast cancer patients located in the NTD impairs HR stimulation on dsDNA/ssDNA junction containing substrates. These findings shed light on the function of the N terminus of BRCA2 and have implications for the evaluation of breast cancer variants.
authors.affiliation: Institut Curie, PSL Research University, UMR 3348, Genotoxic Stress and Cancer Unit, Research Center, Paris Sud University, Paris Saclay University, Centre Universitaire d'Orsay, Bâtiment 110, 91405 Orsay, France.
authors.forename: Catharina
authors.initials: C
authors.lastname: von Nicolai
authors.affiliation: Institut Curie, PSL Research University, UMR 3348, Genotoxic Stress and Cancer Unit, Research Center, Paris Sud University, Paris Saclay University, Centre Universitaire d'Orsay, Bâtiment 110, 91405 Orsay, France.
authors.forename: Åsa
authors.initials: Å
authors.lastname: Ehlén
authors.affiliation: Institut Curie, PSL Research University, UMR 3348, Genotoxic Stress and Cancer Unit, Research Center, Paris Sud University, Paris Saclay University, Centre Universitaire d'Orsay, Bâtiment 110, 91405 Orsay, France.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Martin
authors.affiliation: Department of Medicine, Imperial College London, SAF Building, London SW7 2AZ, UK.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Institut Curie, PSL Research University, UMR 3348, Genotoxic Stress and Cancer Unit, Research Center, Paris Sud University, Paris Saclay University, Centre Universitaire d'Orsay, Bâtiment 110, 91405 Orsay, France.
authors.forename: Aura
authors.initials: A
authors.lastname: Carreira
mesh_terms: D024682:BRCA2 Protein / Q000235:genetics / Q000378:metabolism*; D001943:Breast Neoplasms / Q000235:genetics; D004247:DNA / Q000378:metabolism; D057809:HEK293 Cells; D059765:Homologous Recombination; D006801:Humans; D051135:Rad51 Recombinase / Q000378:metabolism*
chemical_list: D024682:BRCA2 Protein; C551750:BRCA2 protein, human; D004247:DNA; C495153:RAD51 protein, human; D051135:Rad51 Recombinase