The long-term objective of this proposal is to determine the tumor suppressor functions of the hereditary breast/ovarian cancer susceptibility gene, BRCA1. A breast cancer cell line lacking wild-type BRCA1, HCC1937, shows a defect in double strand break repair (DSBR). Wild-type but not cancer-predisposing alleles of BRCA1, stably expressed in HCC1937 cells, correct this defect. This suggests that the DSBR functions of BRCA1 are tumor suppressor functions. Work proposed here will elucidate the function of BRCA1 in DSBR, by use of specific quantitative assays of recombination in HCC1937 cells (Aim 1). To this end, this laboratory has developed a novel recombinational reporter that can positively select for recombination events arising between sister chromatids. The goal is to determine which recombination functions in HCC1937 cells are BRCA1-- dependent (Aim 1) and to perform a genetic analysis of these BRCA1- dependent recombination functions (Aim 2). Defects in recombination frequently cause increased mutation rates in other genes. The mutagenic consequences of BRCA1 dysfunction will be assessed in several parallel systems (Aim 3). This work will therefore significantly advance our understanding of how BRCA1 acts as a tumor suppressor gene.
The specific aims are: 1. To determine the recombinational mechanisms by which wtBRCA1 restores DSBR to HCC1937 cells. 2. To define domains of BRCA1 that are important for recombination. 3. To determine the effect of BRCA1 germline mutation upon the rate and pattern of mutation in other genes.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Special Emphasis Panel (ZRG1-PTHC (01))
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Pelroy, Richard
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Beth Israel Deaconess Medical Center
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Willis, Nicholas A; Panday, Arvind; Duffey, Erin E et al. (2018) Rad51 recruitment and exclusion of non-homologous end joining during homologous recombination at a Tus/Ter mammalian replication fork barrier. PLoS Genet 14:e1007486
Hwang, Yung; Futran, Melinda; Hidalgo, Daniel et al. (2017) Global increase in replication fork speed during a p57KIP2-regulated erythroid cell fate switch. Sci Adv 3:e1700298
Willis, Nicholas A; Frock, Richard L; Menghi, Francesca et al. (2017) Mechanism of tandem duplication formation in BRCA1-mutant cells. Nature 551:590-595
Nath, Sarmi; Somyajit, Kumar; Mishra, Anup et al. (2017) FANCJ helicase controls the balance between short- and long-tract gene conversions between sister chromatids. Nucleic Acids Res 45:8886-8900
Smith, Eric A; Gole, Boris; Willis, Nicholas A et al. (2017) DEK is required for homologous recombination repair of DNA breaks. Sci Rep 7:44662
Menghi, Francesca; Inaki, Koichiro; Woo, XingYi et al. (2016) The tandem duplicator phenotype as a distinct genomic configuration in cancer. Proc Natl Acad Sci U S A 113:E2373-82
Willis, Nicholas A; Scully, Ralph (2016) DNA Polymerase ?: Duct Tape and Zip Ties for a Fragile Genome. Mol Cell 63:542-544
Hartlerode, Andrea J; Willis, Nicholas A; Rajendran, Anbazhagan et al. (2016) Complex Breakpoints and Template Switching Associated with Non-canonical Termination of Homologous Recombination in Mammalian Cells. PLoS Genet 12:e1006410
Guirouilh-Barbat, Josée; Gelot, Camille; Xie, Anyong et al. (2016) 53BP1 Protects against CtIP-Dependent Capture of Ectopic Chromosomal Sequences at the Junction of Distant Double-Strand Breaks. PLoS Genet 12:e1006230
Willis, Nicholas A; Scully, Ralph (2016) Spatial separation of replisome arrest sites influences homologous recombination quality at a Tus/Ter-mediated replication fork barrier. Cell Cycle 15:1812-20

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