The F-Box Domain-Dependent Activity of EMI1 Regulates PARPi Sensitivity in Triple-Negative Breast Cancers.

The BRCA1-BRCA2-RAD51 axis is essential for homologous recombination repair (HRR) and is frequently disrupted in breast cancers. PARP inhibitors (PARPis) are used clinically to treat BRCA-mutated breast tumors. Using a genetic screen, we identified EMI1 as a modulator of PARPi sensitivity in triple-negative breast cancer (TNBC) cells. This function requires ...
the F-box domain of EMI1, through which EMI1 assembles a canonical SCF ubiquitin ligase complex that constitutively targets RAD51 for degradation. In response to genotoxic stress, CHK1-mediated phosphorylation of RAD51 counteracts EMI1-dependent degradation by enhancing RAD51's affinity for BRCA2, leading to RAD51 accumulation. Inhibition of RAD51 degradation restores HRR in BRCA1-depleted cells. Human breast cancer samples display an inverse correlation between EMI1 and RAD51 protein levels. A subset of BRCA1-deficient TNBC cells develop resistance to PARPi by downregulating EMI1 and restoring RAD51-dependent HRR. Notably, reconstitution of EMI1 expression reestablishes PARPi sensitivity both in cellular systems and in an orthotopic mouse model.
Mesh Terms:
Animals, BRCA1 Protein, BRCA2 Protein, Cell Cycle Proteins, Cell Line, Tumor, Checkpoint Kinase 1, DNA Damage, Drug Resistance, Neoplasm, F-Box Proteins, Female, Gene Expression Regulation, Neoplastic, HEK293 Cells, Humans, Mice, Inbred NOD, Mice, SCID, Phosphorylation, Phthalazines, Piperazines, Poly(ADP-ribose) Polymerase Inhibitors, Proteolysis, Rad51 Recombinase, Recombinational DNA Repair, Signal Transduction, Triple Negative Breast Neoplasms, Tumor Burden, Xenograft Model Antitumor Assays
Mol Cell
Date: Jan. 17, 2019
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