Ubiquitin ligase RNF8 suppresses Notch signaling to regulate mammary development and tumorigenesis

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 expressio...

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Bibliographic Details
Authors: Li, Li, Guturi, Kiran Kumar Naidu, Gautreau, Brandon, Patel, Parasvi S., Saad, Amine, Morii, Mayako, Mateo González, Francesca, Palomero, Luis, Barbour, Haithem, Gomez, Antonio, Ng, Deborah, Kotlyar, Max, Pastrello, Chiara, Jackson, Hartland W., Khokha, Rama, Jurisica, Igor, Affar, El Bachir, Raught, Brian, Sanchez, Otto, Alaoui-Jmali, Moulay, Pujana Genestar, M. Ángel, Hakem, Anne, Hakem, Razq
Format: article
Status:Published version
Publication Date:2018
Country:España
Institution:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repository:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:2445/172125
Online Access:https://hdl.handle.net/2445/172125
Access Level:Open access
Keyword:Ubiqüitina
Reparació de l'ADN
Ubiquitin
DNA repair
Description
Summary: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(AOP-ribose) polymerase (PARP), suggesting implications for treatment of breast cancer associated with impaired RNF8 expression or function.

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