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TDP2 suppresses genomic instability induced by androgens in the epithelial cells of prostate glands
Androgens stimulate the proliferation of epithelial cells in the prostate by activating topoisomerase 2 (TOP2) and regulating the transcription of target genes. TOP2 resolves the entanglement of genomic DNA by transiently generating double‐strand breaks (DSBs), where TOP2 homodimers covalently bind...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7497232/ https://www.ncbi.nlm.nih.gov/pubmed/32277721 http://dx.doi.org/10.1111/gtc.12770 |
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author | Al Mahmud, Md. Rasel Ishii, Kenichiro Bernal‐Lozano, Cristina Delgado‐Sainz, Irene Toi, Masakazu Akamatsu, Shusuke Fukumoto, Manabu Watanabe, Masatoshi Takeda, Shunichi Cortés‐Ledesma, Felipe Sasanuma, Hiroyuki |
author_facet | Al Mahmud, Md. Rasel Ishii, Kenichiro Bernal‐Lozano, Cristina Delgado‐Sainz, Irene Toi, Masakazu Akamatsu, Shusuke Fukumoto, Manabu Watanabe, Masatoshi Takeda, Shunichi Cortés‐Ledesma, Felipe Sasanuma, Hiroyuki |
author_sort | Al Mahmud, Md. Rasel |
collection | PubMed |
description | Androgens stimulate the proliferation of epithelial cells in the prostate by activating topoisomerase 2 (TOP2) and regulating the transcription of target genes. TOP2 resolves the entanglement of genomic DNA by transiently generating double‐strand breaks (DSBs), where TOP2 homodimers covalently bind to 5′ DSB ends, called TOP2‐DNA cleavage complexes (TOP2ccs). When TOP2 fails to rejoin TOP2ccs generating stalled TOP2ccs, tyrosyl DNA phosphodiesterase‐2 (TDP2) removes 5′ TOP2 adducts from stalled TOP2ccs prior to the ligation of the DSBs by nonhomologous end joining (NHEJ), the dominant DSB repair pathway in G(0)/G(1) phases. We previously showed that estrogens frequently generate stalled TOP2ccs in G(0)/G(1) phases. Here, we show that physiological concentrations of androgens induce several DSBs in individual human prostate cancer cells during G(1) phase, and loss of TDP2 causes a five times higher number of androgen‐induced chromosome breaks in mitotic chromosome spreads. Intraperitoneally injected androgens induce several DSBs in individual epithelial cells of the prostate in TDP2‐deficient mice, even at 20 hr postinjection. In conclusion, physiological concentrations of androgens have very strong genotoxicity, most likely by generating stalled TOP2ccs. |
format | Online Article Text |
id | pubmed-7497232 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-74972322020-09-25 TDP2 suppresses genomic instability induced by androgens in the epithelial cells of prostate glands Al Mahmud, Md. Rasel Ishii, Kenichiro Bernal‐Lozano, Cristina Delgado‐Sainz, Irene Toi, Masakazu Akamatsu, Shusuke Fukumoto, Manabu Watanabe, Masatoshi Takeda, Shunichi Cortés‐Ledesma, Felipe Sasanuma, Hiroyuki Genes Cells Original Articles Androgens stimulate the proliferation of epithelial cells in the prostate by activating topoisomerase 2 (TOP2) and regulating the transcription of target genes. TOP2 resolves the entanglement of genomic DNA by transiently generating double‐strand breaks (DSBs), where TOP2 homodimers covalently bind to 5′ DSB ends, called TOP2‐DNA cleavage complexes (TOP2ccs). When TOP2 fails to rejoin TOP2ccs generating stalled TOP2ccs, tyrosyl DNA phosphodiesterase‐2 (TDP2) removes 5′ TOP2 adducts from stalled TOP2ccs prior to the ligation of the DSBs by nonhomologous end joining (NHEJ), the dominant DSB repair pathway in G(0)/G(1) phases. We previously showed that estrogens frequently generate stalled TOP2ccs in G(0)/G(1) phases. Here, we show that physiological concentrations of androgens induce several DSBs in individual human prostate cancer cells during G(1) phase, and loss of TDP2 causes a five times higher number of androgen‐induced chromosome breaks in mitotic chromosome spreads. Intraperitoneally injected androgens induce several DSBs in individual epithelial cells of the prostate in TDP2‐deficient mice, even at 20 hr postinjection. In conclusion, physiological concentrations of androgens have very strong genotoxicity, most likely by generating stalled TOP2ccs. John Wiley and Sons Inc. 2020-05-05 2020-07 /pmc/articles/PMC7497232/ /pubmed/32277721 http://dx.doi.org/10.1111/gtc.12770 Text en © 2020 The Authors. Genes to Cells published by Molecular Biology Society of Japan and John Wiley & Sons Australia, Ltd. This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Original Articles Al Mahmud, Md. Rasel Ishii, Kenichiro Bernal‐Lozano, Cristina Delgado‐Sainz, Irene Toi, Masakazu Akamatsu, Shusuke Fukumoto, Manabu Watanabe, Masatoshi Takeda, Shunichi Cortés‐Ledesma, Felipe Sasanuma, Hiroyuki TDP2 suppresses genomic instability induced by androgens in the epithelial cells of prostate glands |
title | TDP2 suppresses genomic instability induced by androgens in the epithelial cells of prostate glands |
title_full | TDP2 suppresses genomic instability induced by androgens in the epithelial cells of prostate glands |
title_fullStr | TDP2 suppresses genomic instability induced by androgens in the epithelial cells of prostate glands |
title_full_unstemmed | TDP2 suppresses genomic instability induced by androgens in the epithelial cells of prostate glands |
title_short | TDP2 suppresses genomic instability induced by androgens in the epithelial cells of prostate glands |
title_sort | tdp2 suppresses genomic instability induced by androgens in the epithelial cells of prostate glands |
topic | Original Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7497232/ https://www.ncbi.nlm.nih.gov/pubmed/32277721 http://dx.doi.org/10.1111/gtc.12770 |
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