Title | The F-Box Domain-Dependent Activity of EMI1 Regulates PARPi Sensitivity in Triple-Negative Breast Cancers. |
Publication Type | Journal Article |
Year of Publication | 2019 |
Authors | Marzio A, Puccini J, Kwon Y, Maverakis NK, Arbini A, Sung P, Bar-Sagi D, Pagano M |
Journal | Mol Cell |
Volume | 73 |
Issue | 2 |
Pagination | 224-237.e6 |
Date Published | 2019 01 17 |
ISSN | 1097-4164 |
Keywords | 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 |
Abstract | 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. |
DOI | 10.1016/j.molcel.2018.11.003 |
Alternate Journal | Mol Cell |
PubMed ID | 30554948 |
PubMed Central ID | PMC6995265 |
Grant List | R01 CA076584 / CA / NCI NIH HHS / United States R01 GM057587 / GM / NIGMS NIH HHS / United States |
Related Lab:
Related Faculty:
Antonio Marzio, Ph.D.