title: The Tumor-Associated Variant RAD51 G151D Induces a Hyper-Recombination Phenotype.
abstract: The RAD51 protein plays a key role in the homology-directed repair of DNA double-strand breaks and is important for maintaining genome stability. Here we report on a novel human RAD51 variant found in an aggressive and therapy-refractive breast carcinoma. Expression of the RAD51 G151D variant in human breast epithelial cells increases the levels of homology-directed repair. Expression of RAD51 G151D in cells also promotes high levels of chromosomal aberrations and sister chromatid exchanges. In vitro, the purified RAD51 G151D protein directly and significantly enhances DNA strand exchange activity in the presence of RPA. In concordance with this result, co-incubation of G151D with BRCA2 resulted in a much higher level of strand-exchange activity compared to WT RAD51. Strikingly, the RAD51 G151D variant confers resistance to multiple DNA damaging agents, including ionizing radiation, mitomycin C, and doxorubicin. Our findings demonstrate that the RAD51 G151D somatic variant has a novel hyper-recombination phenotype and suggest that this property of the protein is important for the repair of DNA damage, leading to drug resistance.
authors: Department of Microbiology and Molecular Genetics, The Markey Center for Molecular Genetics, University of Vermont, Burlington, Vermont, United States of America.
authors: Carolyn G
authors: CG
authors: Marsden
authors: Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, Connecticut, United States of America.
authors: Ryan B
authors: RB
authors: Jensen
authors: Department of Department of Biochemistry and Molecular Pharmacology, NYU School of Medicine, New York, New York, United States of America.
authors: Jennifer
authors: J
authors: Zagelbaum
authors: Department of Department of Biochemistry and Molecular Pharmacology, NYU School of Medicine, New York, New York, United States of America.
authors: Eli
authors: E
authors: Rothenberg
authors: Department of Microbiology and Molecular Genetics, The Markey Center for Molecular Genetics, University of Vermont, Burlington, Vermont, United States of America.|Department of Biochemistry, University of Vermont, Burlington, Vermont, United States of America.
authors: Scott W
authors: SW
authors: Morrical
authors: Department of Microbiology and Molecular Genetics, The Markey Center for Molecular Genetics, University of Vermont, Burlington, Vermont, United States of America.
authors: Susan S
authors: SS
authors: Wallace
authors: Department of Microbiology and Molecular Genetics, The Markey Center for Molecular Genetics, University of Vermont, Burlington, Vermont, United States of America.|Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, Connecticut, United States of America.
authors: Joann B
authors: JB
authors: Sweasy
mesh_terms: D024682:BRCA2 Protein / Q000096:biosynthesis / Q000235:genetics*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology / Q000532:radiotherapy; D002869:Chromosome Aberrations / Q000187:drug effects / Q000528:radiation effects; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects / Q000528:radiation effects; D004249:DNA Damage / Q000187:drug effects / Q000528:radiation effects; D004260:DNA Repair / Q000235:genetics; D004317:Doxorubicin / Q000008:administration & dosage; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics / Q000528:radiation effects; D042822:Genomic Instability / Q000187:drug effects / Q000528:radiation effects; D006801:Humans; D061986:MCF-7 Cells; D016685:Mitomycin / Q000008:administration & dosage; D009154:Mutation; D051135:Rad51 Recombinase / Q000096:biosynthesis / Q000235:genetics*; D011839:Radiation, Ionizing; D059767:Recombinational DNA Repair / Q000235:genetics*; D012854:Sister Chromatid Exchange / Q000235:genetics
chemical_list: D024682:BRCA2 Protein; C551750:BRCA2 protein, human; D016685:Mitomycin; D004317:Doxorubicin; D051135:Rad51 Recombinase