Ubiquitin ligase RNF8 suppresses Notch signaling to regulate mammary development and tumorigenesis
Li Li, … , Anne Hakem, Razq Hakem
Li Li, … , Anne Hakem, Razq Hakem
Published September 17, 2018
Citation Information: J Clin Invest. 2018;128(10):4525-4542. https://doi.org/10.1172/JCI120401.
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Ubiquitin ligase RNF8 suppresses Notch signaling to regulate mammary development and tumorigenesis

Abstract

The E3 ubiquitin ligase RNF8 plays critical roles in maintaining genomic stability by promoting the repair of DNA double-strand breaks (DSBs) through ubiquitin signaling. Abnormal activation of Notch signaling and defective repair of DSBs promote breast cancer risk. Here, we found that low expression of the full-length RNF8 correlated with poor prognosis for breast cancer patients. Our data revealed that in addition to its role in the repair of DSBs, RNF8 regulated Notch1 signaling and cell-fate determination of mammary luminal progenitors. Mechanistically, RNF8 acted as a negative regulator of Notch signaling by ubiquitylating the active NOTCH1 protein (N1ICD), leading to its degradation. Consistent with abnormal activation of Notch signaling and impaired repair of DSBs in Rnf8-mutant mammary epithelial cells, we observed increased risk of mammary tumorigenesis in mouse models for RNF8 deficiency. Notably, deficiency of RNF8 sensitized breast cancer cells to combination of pharmacological inhibitors of Notch signaling and poly(ADP-ribose) polymerase (PARP), suggesting implications for treatment of breast cancer associated with impaired RNF8 expression or function.

Authors

Li Li, Kiran Kumar Naidu Guturi, Brandon Gautreau, Parasvi S. Patel, Amine Saad, Mayako Morii, Francesca Mateo, Luis Palomero, Haithem Barbour, Antonio Gomez, Deborah Ng, Max Kotlyar, Chiara Pastrello, Hartland W. Jackson, Rama Khokha, Igor Jurisica, El Bachir Affar, Brian Raught, Otto Sanchez, Moulay Alaoui-Jamali, Miguel A. Pujana, Anne Hakem, Razq Hakem

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Figure 9

A schematic diagram depicting a model for RNF8-mediated coregulation of Notch signaling and DSB repair and the breast cancer–suppressive function of RNF8.

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A schematic diagram depicting a model for RNF8-mediated coregulation of ...
RNF8 is recruited to DSBs, where it ubiquitylates histones at the flanking DNA damage sites. This ubiquitylation triggers recruitment of downstream DSB signaling and repair proteins (e.g., RNF168 and BRCA1) to DNA damage sites, allowing their repair. Loss of RNF8 expression or function impairs DSB repair, leading to genomic instability and increased breast cancer risk. Our data reveal an important role for RNF8 in mediating negative regulation of Notch signaling. RNF8 ubiquitylates the active form of NOTCH1 (N1ICD) to promote its turnover. Thus, impaired RNF8 expression or function results in constitutive activation of Notch signaling in mammary luminal progenitors, a process that promotes expansion of these progenitors and increases their risk for malignant transformation. We propose that RNF8 coregulation of Notch signaling and DSB repair is critical for its suppressor function in breast cancer. Small filled circles indicate γH2ax (black); phosphorylation (gray); and Ub (red).