Open AccessThe Tumor-Associated Variant RAD51 G151D Induces a Hyper-Recombination Phenotype
Author(s) -
Carolyn G. Marsden,
Ryan B. Jensen,
Jennifer Zagelbaum,
Eli Rothenberg,
Scott W. Morrical,
Susan S. Wallace,
Joann B. Sweasy
Publication year - 2016
Publication title -
plos genetics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.587
H-Index - 233
eISSN - 1553-7404
pISSN - 1553-7390
DOI - 10.1371/journal.pgen.1006208
Subject(s) - rad51 , biology , homologous recombination , dna repair , microbiology and biotechnology , dna damage , rad52 , homology directed repair , dna , mitomycin c , genetics , cancer research , dna mismatch repair
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.