Format

Send to

Choose Destination
Mol Cell. 2019 Jan 17;73(2):224-237.e6. doi: 10.1016/j.molcel.2018.11.003. Epub 2018 Dec 13.

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

Author information

1
Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY 10016, USA; Perlmutter NYU Cancer Center, New York University School of Medicine, New York, NY 10016, USA.
2
Department of Biochemistry and Structural Biology, UT Health San Antonio, San Antonio, TX 78229, USA.
3
Perlmutter NYU Cancer Center, New York University School of Medicine, New York, NY 10016, USA; Department of Pathology, New York University School of Medicine, New York, NY 10016, USA.
4
Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY 10016, USA; Perlmutter NYU Cancer Center, New York University School of Medicine, New York, NY 10016, USA; Howard Hughes Medical Institute, New York University School of Medicine, New York, NY 10016, USA. Electronic address: michele.pagano@nyumc.org.

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.

KEYWORDS:

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

PMID:
30554948
DOI:
10.1016/j.molcel.2018.11.003
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Elsevier Science Icon for NYU School of Medicine
Loading ...
Support Center