Inherited mutations in the Breast Cancer 1 and 2 genes (BRCA1 and BRCA2) confer susceptibility to breast and ovarian cancer, as well as to pancreatic and prostate cancers. The BRCA proteins are required for DNA repair by homologous recombination and this function is intimately connected to tumor suppression. BRCA mutation status is also an important predictor of response to chemotherapy. Inhibition of specific DNA repair pathways has emerged as an elegant and effective strategy to induce synthetic lethality in BRCA mutant cancers. Understanding the molecular basis of BRCA dependent DNA repair is therefore a central issue to cancer etiology and therapy. We have discovered that BRCA1 is targeted to lysine63-linked ubiquitin regions aligning DNA double-strand break chromatin by the RAP80-BRCC36 complex. Deficiency of this complex results in reduced BRCA1 DNA damage localization and genomic instability. Moreover, mutations within several genes that encode constituents of this complex are associated with familial breast cancer. This indicates that ubiquitin recognition at double-strand break chromatin is a bona fide component of BRCA dependent tumor suppression. This proposal will take in vivo, cellular, and structure guided biochemical approaches to understand how DNA double-strand break ubiquitin recognition by the RAP80-BRCC36 complex relates to BRCA dependent homologous recombination repair mechanisms and response to therapy. The studies are intended to elucidate basic DNA repair mechanisms and gain insights into cancer etiology and therapy.
A biochemical interaction between the breast and ovarian cancer suppressor protein BRCA1 and the RAP80-BRCC36 complex is critical to the maintenance of genome integrity and tumor suppression. Three members of the RAP80-BRCC36 complex are mutated in familial breast cancer, validating ubiquitin recognition as a bona fide tumor suppressor mechanism. It is therefore of central importance to understand the relationship of the RAP80-BRCC36 complex to BRCA dependent DNA repair mechanisms.
|Harding, Shane M; Benci, Joseph L; Irianto, Jerome et al. (2017) Mitotic progression following DNA damage enables pattern recognition within micronuclei. Nature 548:466-470|
|Cho, Nam Woo; Lampson, Michael A; Greenberg, Roger A (2017) In vivo imaging of DNA double-strand break induced telomere mobility during alternative lengthening of telomeres. Methods 114:54-59|
|Irianto, Jerome; Xia, Yuntao; Pfeifer, Charlotte R et al. (2017) DNA Damage Follows Repair Factor Depletion and Portends Genome Variation in Cancer Cells after Pore Migration. Curr Biol 27:210-223|
|Zahn, Karl E; Greenberg, Roger A (2017) Putting PHDs to work: PHF11 clears the way for EXO1 in double-strand break repair. Genes Dev 31:3-5|
|Verma, Priyanka; Greenberg, Roger A (2016) Noncanonical views of homology-directed DNA repair. Genes Dev 30:1138-54|
|Dilley, Robert L; Verma, Priyanka; Cho, Nam Woo et al. (2016) Break-induced telomere synthesis underlies alternative telomere maintenance. Nature 539:54-58|
|Edmonds, Christine E; Makvandi, Mehran; Lieberman, Brian P et al. (2016) [(18)F]FluorThanatrace uptake as a marker of PARP1 expression and activity in breast cancer. Am J Nucl Med Mol Imaging 6:94-101|
|Harding, Shane M; Greenberg, Roger A (2016) Choreographing the Double Strand Break Response: Ubiquitin and SUMO Control of Nuclear Architecture. Front Genet 7:103|
|Makvandi, Mehran; Xu, Kuiying; Lieberman, Brian P et al. (2016) A Radiotracer Strategy to Quantify PARP-1 Expression In Vivo Provides a Biomarker That Can Enable Patient Selection for PARP Inhibitor Therapy. Cancer Res 76:4516-24|
|Harding, Shane M; Boiarsky, Jonathan A; Greenberg, Roger A (2015) ATM Dependent Silencing Links Nucleolar Chromatin Reorganization to DNA Damage Recognition. Cell Rep 13:251-9|
Showing the most recent 10 out of 33 publications