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

William I. Towler, Jie Zhang, Derek J.R. Ransburgh, Amanda E. Toland, Chikashi Ishioka, Natsuko Chiba, Jeffrey D. Parvin

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

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. 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 or ovarian cancer. In this study, we evaluated whether functional assays for DNA repair can augment the genetic information. We found that the effects of BRCA1 missense substitutions on protein function in homologous recombination repair of DNA double strand breaks were predictive of disease association.

Original languageEnglish (US)
Pages (from-to)439-445
Number of pages7
JournalHuman Mutation
Volume34
Issue number3
DOIs
StatePublished - Mar 1 2013
Externally publishedYes

Fingerprint

Recombinational DNA Repair
Genetic Recombination
DNA Repair
BRCA1 Gene
Genetic Counseling
Breast Neoplasms
BRCA1 Protein
Ovarian Neoplasms
Amino Acids
Mutation
Proteins

Keywords

  • BRCA1
  • Centrosome
  • Homologous recombination
  • Single-strand annealing
  • VUS

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Towler, W. I., Zhang, J., Ransburgh, D. J. R., Toland, A. E., Ishioka, C., Chiba, N., & Parvin, J. D. (2013). Analysis of BRCA1 Variants in Double-Strand Break Repair by Homologous Recombination and Single-Strand Annealing. Human Mutation, 34(3), 439-445. https://doi.org/10.1002/humu.22251

Analysis of BRCA1 Variants in Double-Strand Break Repair by Homologous Recombination and Single-Strand Annealing. / Towler, William I.; Zhang, Jie; Ransburgh, Derek J.R.; Toland, Amanda E.; Ishioka, Chikashi; Chiba, Natsuko; Parvin, Jeffrey D.

In: Human Mutation, Vol. 34, No. 3, 01.03.2013, p. 439-445.

Research output: Contribution to journalArticle

Towler, WI, Zhang, J, Ransburgh, DJR, Toland, AE, Ishioka, C, Chiba, N & Parvin, JD 2013, 'Analysis of BRCA1 Variants in Double-Strand Break Repair by Homologous Recombination and Single-Strand Annealing', Human Mutation, vol. 34, no. 3, pp. 439-445. https://doi.org/10.1002/humu.22251
Towler, William I. ; Zhang, Jie ; Ransburgh, Derek J.R. ; Toland, Amanda E. ; Ishioka, Chikashi ; Chiba, Natsuko ; Parvin, Jeffrey D. / Analysis of BRCA1 Variants in Double-Strand Break Repair by Homologous Recombination and Single-Strand Annealing. In: Human Mutation. 2013 ; Vol. 34, No. 3. pp. 439-445.
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