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Title: Ubiquitin ligase RNF8 suppresses Notch signaling to regulate mammary development and tumorigenesis
Author: 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
Keywords: Ubiqüitina
Reparació de l'ADN
DNA repair
Issue Date: 1-Oct-2018
Publisher: American Society Clinical Investigation Inc.
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(AOP-ribose) polymerase (PARP), suggesting implications for treatment of breast cancer associated with impaired RNF8 expression or function.
Note: Reproducció del document publicat a:
It is part of: Journal of Clinical Investigation, 2018, vol. 128, num. 10, p. 4525-4542
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Appears in Collections:Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))

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