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

The Journal of Clinical Investigation
Li LiRazq Hakem

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.

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Citations

Nov 6, 2018·Biomedicines·Eike-Benjamin BrauneUrban Lendahl
Feb 3, 2021·The Journal of Clinical Investigation·Parasvi S PatelRazqallah Hakem
Mar 2, 2021·The FEBS Journal·Debdeep DuttaAshim Mukherjee

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Datasets Mentioned

BETA
MDA-MB-231
GSE76075

Methods Mentioned

BETA
PCR
transfection
flow cytometry
reverse transcription PCR
RNA-Seq
immunoprecipitation

Software Mentioned

DESeq2 R package
Sequence Detection System
Ensembl
Bioconductor
BEDTools multicov
STAR
SAMtools
Kaplan Plotter (
KM Plotter
FlowJo

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