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Wwox–Brca1 interaction: role in DNA repair pathway choice

In this study, loss of expression of the fragile site-encoded Wwox protein was found to contribute to radiation and cisplatin resistance of cells, responses that could be associated with cancer recurrence and poor outcome. WWOX gene deletions occur in a variety of human cancer types, and reduced Wwo...

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Autores principales: Schrock, M S, Batar, B, Lee, J, Druck, T, Ferguson, B, Cho, J H, Akakpo, K, Hagrass, H, Heerema, N A, Xia, F, Parvin, J D, Aldaz, C M, Huebner, K
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5398941/
https://www.ncbi.nlm.nih.gov/pubmed/27869163
http://dx.doi.org/10.1038/onc.2016.389
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author Schrock, M S
Batar, B
Lee, J
Druck, T
Ferguson, B
Cho, J H
Akakpo, K
Hagrass, H
Heerema, N A
Xia, F
Parvin, J D
Aldaz, C M
Huebner, K
author_facet Schrock, M S
Batar, B
Lee, J
Druck, T
Ferguson, B
Cho, J H
Akakpo, K
Hagrass, H
Heerema, N A
Xia, F
Parvin, J D
Aldaz, C M
Huebner, K
author_sort Schrock, M S
collection PubMed
description In this study, loss of expression of the fragile site-encoded Wwox protein was found to contribute to radiation and cisplatin resistance of cells, responses that could be associated with cancer recurrence and poor outcome. WWOX gene deletions occur in a variety of human cancer types, and reduced Wwox protein expression can be detected early during cancer development. We found that Wwox loss is followed by mild chromosome instability in genomes of mouse embryo fibroblast cells from Wwox-knockout mice. Human and mouse cells deficient for Wwox also exhibit significantly enhanced survival of ionizing radiation and bleomycin treatment, agents that induce double-strand breaks (DSBs). Cancer cells that survive radiation recur more rapidly in a xenograft model of irradiated breast cancer cells; Wwox-deficient cells exhibited significantly shorter tumor latencies vs Wwox-expressing cells. This Wwox effect has important consequences in human disease: in a cohort of cancer patients treated with radiation, Wwox deficiency significantly correlated with shorter overall survival times. In examining mechanisms underlying Wwox-dependent survival differences, we found that Wwox-deficient cells exhibit enhanced homology directed repair (HDR) and decreased non-homologous end-joining (NHEJ) repair, suggesting that Wwox contributes to DNA DSB repair pathway choice. Upon silencing of Rad51, a protein critical for HDR, Wwox-deficient cells were resensitized to radiation. We also demonstrated interaction of Wwox with Brca1, a driver of HDR, and show via immunofluorescent detection of repair proteins at ionizing radiation-induced DNA damage foci that Wwox expression suppresses DSB repair at the end-resection step of HDR. We propose a genome caretaker function for WWOX, in which Brca1–Wwox interaction supports NHEJ as the dominant DSB repair pathway in Wwox-sufficient cells. Taken together, the experimental results suggest that reduced Wwox expression, a common occurrence in cancers, dysregulates DSB repair, enhancing efficiency of likely mutagenic repair, and enabling radiation and cisplatin treatment resistance.
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spelling pubmed-53989412017-05-18 Wwox–Brca1 interaction: role in DNA repair pathway choice Schrock, M S Batar, B Lee, J Druck, T Ferguson, B Cho, J H Akakpo, K Hagrass, H Heerema, N A Xia, F Parvin, J D Aldaz, C M Huebner, K Oncogene Original Article In this study, loss of expression of the fragile site-encoded Wwox protein was found to contribute to radiation and cisplatin resistance of cells, responses that could be associated with cancer recurrence and poor outcome. WWOX gene deletions occur in a variety of human cancer types, and reduced Wwox protein expression can be detected early during cancer development. We found that Wwox loss is followed by mild chromosome instability in genomes of mouse embryo fibroblast cells from Wwox-knockout mice. Human and mouse cells deficient for Wwox also exhibit significantly enhanced survival of ionizing radiation and bleomycin treatment, agents that induce double-strand breaks (DSBs). Cancer cells that survive radiation recur more rapidly in a xenograft model of irradiated breast cancer cells; Wwox-deficient cells exhibited significantly shorter tumor latencies vs Wwox-expressing cells. This Wwox effect has important consequences in human disease: in a cohort of cancer patients treated with radiation, Wwox deficiency significantly correlated with shorter overall survival times. In examining mechanisms underlying Wwox-dependent survival differences, we found that Wwox-deficient cells exhibit enhanced homology directed repair (HDR) and decreased non-homologous end-joining (NHEJ) repair, suggesting that Wwox contributes to DNA DSB repair pathway choice. Upon silencing of Rad51, a protein critical for HDR, Wwox-deficient cells were resensitized to radiation. We also demonstrated interaction of Wwox with Brca1, a driver of HDR, and show via immunofluorescent detection of repair proteins at ionizing radiation-induced DNA damage foci that Wwox expression suppresses DSB repair at the end-resection step of HDR. We propose a genome caretaker function for WWOX, in which Brca1–Wwox interaction supports NHEJ as the dominant DSB repair pathway in Wwox-sufficient cells. Taken together, the experimental results suggest that reduced Wwox expression, a common occurrence in cancers, dysregulates DSB repair, enhancing efficiency of likely mutagenic repair, and enabling radiation and cisplatin treatment resistance. Nature Publishing Group 2017-04-20 2016-11-21 /pmc/articles/PMC5398941/ /pubmed/27869163 http://dx.doi.org/10.1038/onc.2016.389 Text en Copyright © 2017 The Author(s) http://creativecommons.org/licenses/by-nc-nd/4.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0/
spellingShingle Original Article
Schrock, M S
Batar, B
Lee, J
Druck, T
Ferguson, B
Cho, J H
Akakpo, K
Hagrass, H
Heerema, N A
Xia, F
Parvin, J D
Aldaz, C M
Huebner, K
Wwox–Brca1 interaction: role in DNA repair pathway choice
title Wwox–Brca1 interaction: role in DNA repair pathway choice
title_full Wwox–Brca1 interaction: role in DNA repair pathway choice
title_fullStr Wwox–Brca1 interaction: role in DNA repair pathway choice
title_full_unstemmed Wwox–Brca1 interaction: role in DNA repair pathway choice
title_short Wwox–Brca1 interaction: role in DNA repair pathway choice
title_sort wwox–brca1 interaction: role in dna repair pathway choice
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5398941/
https://www.ncbi.nlm.nih.gov/pubmed/27869163
http://dx.doi.org/10.1038/onc.2016.389
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