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

Antonio Marzio, Joseph Puccini, Youngho Kwon, Natalia K. Maverakis, Arnaldo Arbini, Patrick Sung, Dafna Bar-Sagi, Michele Pagano

Research output: Contribution to journalArticle

14 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)224-237.e6
JournalMolecular Cell
Volume73
Issue number2
DOIs
StatePublished - Jan 17 2019

Keywords

  • BRCA1
  • CHK1
  • DNA damage
  • EMI1
  • HRR
  • PARPi resistance
  • RAD51
  • breast cancer
  • proteolysis
  • ubiquitin

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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