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A phosphorylation–deubiquitination cascade regulates the BRCA2–RAD51 axis in homologous recombination

Homologous recombination (HR) is one of the major DNA double-strand break (DSB) repair pathways in mammalian cells. Defects in HR trigger genomic instability and result in cancer predisposition. The defining step of HR is homologous strand exchange directed by the protein RAD51, which is recruited t...

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Autores principales: Luo, Kuntian, Li, Lei, Li, Yunhui, Wu, Chenming, Yin, Yujiao, Chen, Yuping, Deng, Min, Nowsheen, Somaira, Yuan, Jian, Lou, Zhenkun
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory Press 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5204351/
https://www.ncbi.nlm.nih.gov/pubmed/27941124
http://dx.doi.org/10.1101/gad.289439.116
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author Luo, Kuntian
Li, Lei
Li, Yunhui
Wu, Chenming
Yin, Yujiao
Chen, Yuping
Deng, Min
Nowsheen, Somaira
Yuan, Jian
Lou, Zhenkun
author_facet Luo, Kuntian
Li, Lei
Li, Yunhui
Wu, Chenming
Yin, Yujiao
Chen, Yuping
Deng, Min
Nowsheen, Somaira
Yuan, Jian
Lou, Zhenkun
author_sort Luo, Kuntian
collection PubMed
description Homologous recombination (HR) is one of the major DNA double-strand break (DSB) repair pathways in mammalian cells. Defects in HR trigger genomic instability and result in cancer predisposition. The defining step of HR is homologous strand exchange directed by the protein RAD51, which is recruited to DSBs by BRCA2. However, the regulation of the BRCA2–RAD51 axis remains unclear. Here we report that ubiquitination of RAD51 hinders RAD51–BRCA2 interaction, while deubiquitination of RAD51 facilitates RAD51–BRCA2 binding and RAD51 recruitment and thus is critical for proper HR. Mechanistically, in response to DNA damage, the deubiquitinase UCHL3 is phosphorylated and activated by ATM. UCHL3, in turn, deubiquitinates RAD51 and promotes the binding between RAD51 and BRCA2. Overexpression of UCHL3 renders breast cancer cells resistant to radiation and chemotherapy, while depletion of UCHL3 sensitizes cells to these treatments, suggesting a determinant role of UCHL3 in cancer therapy. Overall, we identify UCHL3 as a novel regulator of DNA repair and reveal a model in which a phosphorylation–deubiquitination cascade dynamically regulates the BRCA2–RAD51 pathway.
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spelling pubmed-52043512017-06-01 A phosphorylation–deubiquitination cascade regulates the BRCA2–RAD51 axis in homologous recombination Luo, Kuntian Li, Lei Li, Yunhui Wu, Chenming Yin, Yujiao Chen, Yuping Deng, Min Nowsheen, Somaira Yuan, Jian Lou, Zhenkun Genes Dev Research Paper Homologous recombination (HR) is one of the major DNA double-strand break (DSB) repair pathways in mammalian cells. Defects in HR trigger genomic instability and result in cancer predisposition. The defining step of HR is homologous strand exchange directed by the protein RAD51, which is recruited to DSBs by BRCA2. However, the regulation of the BRCA2–RAD51 axis remains unclear. Here we report that ubiquitination of RAD51 hinders RAD51–BRCA2 interaction, while deubiquitination of RAD51 facilitates RAD51–BRCA2 binding and RAD51 recruitment and thus is critical for proper HR. Mechanistically, in response to DNA damage, the deubiquitinase UCHL3 is phosphorylated and activated by ATM. UCHL3, in turn, deubiquitinates RAD51 and promotes the binding between RAD51 and BRCA2. Overexpression of UCHL3 renders breast cancer cells resistant to radiation and chemotherapy, while depletion of UCHL3 sensitizes cells to these treatments, suggesting a determinant role of UCHL3 in cancer therapy. Overall, we identify UCHL3 as a novel regulator of DNA repair and reveal a model in which a phosphorylation–deubiquitination cascade dynamically regulates the BRCA2–RAD51 pathway. Cold Spring Harbor Laboratory Press 2016-12-01 /pmc/articles/PMC5204351/ /pubmed/27941124 http://dx.doi.org/10.1101/gad.289439.116 Text en © 2016 Luo et al.; Published by Cold Spring Harbor Laboratory Press http://creativecommons.org/licenses/by-nc/4.0/ This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genesdev.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.
spellingShingle Research Paper
Luo, Kuntian
Li, Lei
Li, Yunhui
Wu, Chenming
Yin, Yujiao
Chen, Yuping
Deng, Min
Nowsheen, Somaira
Yuan, Jian
Lou, Zhenkun
A phosphorylation–deubiquitination cascade regulates the BRCA2–RAD51 axis in homologous recombination
title A phosphorylation–deubiquitination cascade regulates the BRCA2–RAD51 axis in homologous recombination
title_full A phosphorylation–deubiquitination cascade regulates the BRCA2–RAD51 axis in homologous recombination
title_fullStr A phosphorylation–deubiquitination cascade regulates the BRCA2–RAD51 axis in homologous recombination
title_full_unstemmed A phosphorylation–deubiquitination cascade regulates the BRCA2–RAD51 axis in homologous recombination
title_short A phosphorylation–deubiquitination cascade regulates the BRCA2–RAD51 axis in homologous recombination
title_sort phosphorylation–deubiquitination cascade regulates the brca2–rad51 axis in homologous recombination
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5204351/
https://www.ncbi.nlm.nih.gov/pubmed/27941124
http://dx.doi.org/10.1101/gad.289439.116
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