Analysis of BRCA1 Variants in Double-Strand Break Repair by Homologous Recombination and Single-Strand Annealing

By W. I. Towler, Jie Zhang, Derek J. R. Ransburgh, A. Toland, Chikashi Ishioka, N. Chiba, Jeffrey D. Parvin. 2012

59 citations recorded by the source corpus.

Missense substitutions of uncertain clinical significance in the BRCA1 gene are a vexing problem in genetic counseling for women who have a family history of breast cancer. In this study, we evaluated the functions of 29 missense substitutions of BRCA1 in two DNA repair pathways. Repair of double‐strand breaks by homology‐directed recombination (HDR) had been previously analyzed for 16 of these BRCA1 variants, and 13 more variants were analyzed in this study. All 29 variants were also analyzed for function in double‐strand break repair by the single‐strand annealing (SSA) pathway. We found that among the pathogenic mutations in BRCA1, all were defective for DNA repair by either pathway. The HDR assay was accurate because all pathogenic mutants were defective for HDR, and all nonpathogenic variants were fully functional for HDR. Repair by SSA accurately identified pathogenic mutants, but several nonpathogenic variants were scored as defective or partially defective. These results indicated that specific amino acid residues of the BRCA1 protein have different effects in the two related DNA repair pathways, and these results validate the HDR assay as highly correlative with BRCA1‐associated breast cancer.

Subfields: Genetics, Molecular Biology

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Citations in the corpus

Homologous recombination and human health: the roles of BRCA1, BRCA2 and associated proteins (2015, background): “Multiple breast cancer and engineered mutations in BRCA1 have been shown to confer defects in HR, connecting the HR and cancer suppressor roles of BRCA1 (Ruffner et al. 2001; Sy et al. 2009; Drost et al. 2011; Towler et al. 2013).”
Massively Parallel Functional Analysis of BRCA1 RING Domain Variants (2015, methodology): “Copyright © 2015 by the Genetics Society of America doi: 10.1534/genetics.115.175802 Manuscript received February 23, 2015; accepted for publication March 1, 2015; published Early Online March 30, 2015.”