RNF126 promotes homologous recombination via regulation of E2F1-mediated BRCA1 expression

RNF126 promotes homologous recombination via regulation of E2F1-mediated BRCA1 expression

RNF126 is an E3 ubiquitin ligase. The deletion of RNF126 gene was observed in a wide range of human cancers and is correlated with improved disease-free and overall survival. These data highlights the clinical relevance of RNF126 in tumorigenesis and cancer therapy. However, the specific functions o...

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Main Authors: Wang, Ying, Deng, Ou, Feng, Zhihui, Du, Zhanwen, Xiong, Xiahui, Lai, Jinzhi, Yang, Xiaosong, Xu, Mengyuan, Wang, Hongbing, Taylor, Derek, Yan, Chunhong, Chen, Ceshi, Difeo, Analisa, Ma, Zhefu, Zhang, Junran
Format: Online
Language:English
Published: 2015
Online Access:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4740281/
id pubmed-4740281
recordtype oai_dc
spelling pubmed-47402812016-05-18 RNF126 promotes homologous recombination via regulation of E2F1-mediated BRCA1 expression Wang, Ying Deng, Ou Feng, Zhihui Du, Zhanwen Xiong, Xiahui Lai, Jinzhi Yang, Xiaosong Xu, Mengyuan Wang, Hongbing Taylor, Derek Yan, Chunhong Chen, Ceshi Difeo, Analisa Ma, Zhefu Zhang, Junran Article RNF126 is an E3 ubiquitin ligase. The deletion of RNF126 gene was observed in a wide range of human cancers and is correlated with improved disease-free and overall survival. These data highlights the clinical relevance of RNF126 in tumorigenesis and cancer therapy. However, the specific functions of RNF126 remain largely unknown. Homologous recombination (HR)-mediated DNA double-strand break repair is important for tumor suppression and cancer therapy resistance. Here, we demonstrate that RNF126 facilitates HR by promoting the expression of BRCA1, in a manner independent of its E3 ligase activity but depending on E2F1, a well-known transcription factor of BRCA1 promoter. In support of this result, RNF126 promotes transactivation of BRCA1 promoter by directly binding to E2F1. Most importantly, an RNF126 mutant lacking 11 amino acids that is responsible for the interaction with E2F1 has a dominant-negative effect on BRCA1 expression and HR by suppressing E2F1-mediated transactivation of BRCA1 promoter and blocking the enrichment of E2F1 on BRCA1 promoter. Lastly, RNF126 depletion leads to the increased sensitivity to ionizing radiation (IR) and poly (ADP-ribose) polymerase (PARP) inhibition. Collectively, our results suggest a novel role of RNF126 in promoting HR-mediated repair through positive regulation on BRCA1 expression by direct interaction with E2F1. This study not only offers novel insights into our current understanding of the biological functions of RNF126 but also provides a potential therapeutic target for cancer treatment. 2015-08-03 2016-03-17 /pmc/articles/PMC4740281/ /pubmed/26234677 http://dx.doi.org/10.1038/onc.2015.198 Text en http://www.nature.com/authors/editorial_policies/license.html#terms Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms
repository_type Open Access Journal
institution_category Foreign Institution
institution US National Center for Biotechnology Information
building NCBI PubMed
collection Online Access
language English
format Online
author Wang, Ying
Deng, Ou
Feng, Zhihui
Du, Zhanwen
Xiong, Xiahui
Lai, Jinzhi
Yang, Xiaosong
Xu, Mengyuan
Wang, Hongbing
Taylor, Derek
Yan, Chunhong
Chen, Ceshi
Difeo, Analisa
Ma, Zhefu
Zhang, Junran
spellingShingle Wang, Ying
Deng, Ou
Feng, Zhihui
Du, Zhanwen
Xiong, Xiahui
Lai, Jinzhi
Yang, Xiaosong
Xu, Mengyuan
Wang, Hongbing
Taylor, Derek
Yan, Chunhong
Chen, Ceshi
Difeo, Analisa
Ma, Zhefu
Zhang, Junran
RNF126 promotes homologous recombination via regulation of E2F1-mediated BRCA1 expression
author_facet Wang, Ying
Deng, Ou
Feng, Zhihui
Du, Zhanwen
Xiong, Xiahui
Lai, Jinzhi
Yang, Xiaosong
Xu, Mengyuan
Wang, Hongbing
Taylor, Derek
Yan, Chunhong
Chen, Ceshi
Difeo, Analisa
Ma, Zhefu
Zhang, Junran
author_sort Wang, Ying
title RNF126 promotes homologous recombination via regulation of E2F1-mediated BRCA1 expression
title_short RNF126 promotes homologous recombination via regulation of E2F1-mediated BRCA1 expression
title_full RNF126 promotes homologous recombination via regulation of E2F1-mediated BRCA1 expression
title_fullStr RNF126 promotes homologous recombination via regulation of E2F1-mediated BRCA1 expression
title_full_unstemmed RNF126 promotes homologous recombination via regulation of E2F1-mediated BRCA1 expression
title_sort rnf126 promotes homologous recombination via regulation of e2f1-mediated brca1 expression
description RNF126 is an E3 ubiquitin ligase. The deletion of RNF126 gene was observed in a wide range of human cancers and is correlated with improved disease-free and overall survival. These data highlights the clinical relevance of RNF126 in tumorigenesis and cancer therapy. However, the specific functions of RNF126 remain largely unknown. Homologous recombination (HR)-mediated DNA double-strand break repair is important for tumor suppression and cancer therapy resistance. Here, we demonstrate that RNF126 facilitates HR by promoting the expression of BRCA1, in a manner independent of its E3 ligase activity but depending on E2F1, a well-known transcription factor of BRCA1 promoter. In support of this result, RNF126 promotes transactivation of BRCA1 promoter by directly binding to E2F1. Most importantly, an RNF126 mutant lacking 11 amino acids that is responsible for the interaction with E2F1 has a dominant-negative effect on BRCA1 expression and HR by suppressing E2F1-mediated transactivation of BRCA1 promoter and blocking the enrichment of E2F1 on BRCA1 promoter. Lastly, RNF126 depletion leads to the increased sensitivity to ionizing radiation (IR) and poly (ADP-ribose) polymerase (PARP) inhibition. Collectively, our results suggest a novel role of RNF126 in promoting HR-mediated repair through positive regulation on BRCA1 expression by direct interaction with E2F1. This study not only offers novel insights into our current understanding of the biological functions of RNF126 but also provides a potential therapeutic target for cancer treatment.
publishDate 2015
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4740281/
_version_ 1613533271056973824

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