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Metnase Mediates Resistance to Topoisomerase II Inhibitors in Breast Cancer Cells

DNA replication produces tangled, or catenated, chromatids, that must be decatenated prior to mitosis or catastrophic genomic damage will occur. Topoisomerase IIα (Topo IIα) is the primary decatenating enzyme. Cells monitor catenation status and activate decatenation checkpoints when decatenation is...

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Autores principales: Wray, Justin, Williamson, Elizabeth A., Royce, Melanie, Shaheen, Montaser, Beck, Brian D., Lee, Suk-Hee, Nickoloff, Jac A., Hromas, Robert
Formato: Texto
Lenguaje:English
Publicado: Public Library of Science 2009
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2669129/
https://www.ncbi.nlm.nih.gov/pubmed/19390626
http://dx.doi.org/10.1371/journal.pone.0005323
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author Wray, Justin
Williamson, Elizabeth A.
Royce, Melanie
Shaheen, Montaser
Beck, Brian D.
Lee, Suk-Hee
Nickoloff, Jac A.
Hromas, Robert
author_facet Wray, Justin
Williamson, Elizabeth A.
Royce, Melanie
Shaheen, Montaser
Beck, Brian D.
Lee, Suk-Hee
Nickoloff, Jac A.
Hromas, Robert
author_sort Wray, Justin
collection PubMed
description DNA replication produces tangled, or catenated, chromatids, that must be decatenated prior to mitosis or catastrophic genomic damage will occur. Topoisomerase IIα (Topo IIα) is the primary decatenating enzyme. Cells monitor catenation status and activate decatenation checkpoints when decatenation is incomplete, which occurs when Topo IIα is inhibited by chemotherapy agents such as the anthracyclines and epididophyllotoxins. We recently demonstrated that the DNA repair component Metnase (also called SETMAR) enhances Topo IIα-mediated decatenation, and hypothesized that Metnase could mediate resistance to Topo IIα inhibitors. Here we show that Metnase interacts with Topo IIα in breast cancer cells, and that reducing Metnase expression significantly increases metaphase decatenation checkpoint arrest. Repression of Metnase sensitizes breast cancer cells to Topo IIα inhibitors, and directly blocks the inhibitory effect of the anthracycline adriamycin on Topo IIα-mediated decatenation in vitro. Thus, Metnase may mediate resistance to Topo IIα inhibitors, and could be a biomarker for clinical sensitivity to anthracyclines. Metnase could also become an important target for combination chemotherapy with current Topo IIα inhibitors, specifically in anthracycline-resistant breast cancer.
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spelling pubmed-26691292009-04-24 Metnase Mediates Resistance to Topoisomerase II Inhibitors in Breast Cancer Cells Wray, Justin Williamson, Elizabeth A. Royce, Melanie Shaheen, Montaser Beck, Brian D. Lee, Suk-Hee Nickoloff, Jac A. Hromas, Robert PLoS One Research Article DNA replication produces tangled, or catenated, chromatids, that must be decatenated prior to mitosis or catastrophic genomic damage will occur. Topoisomerase IIα (Topo IIα) is the primary decatenating enzyme. Cells monitor catenation status and activate decatenation checkpoints when decatenation is incomplete, which occurs when Topo IIα is inhibited by chemotherapy agents such as the anthracyclines and epididophyllotoxins. We recently demonstrated that the DNA repair component Metnase (also called SETMAR) enhances Topo IIα-mediated decatenation, and hypothesized that Metnase could mediate resistance to Topo IIα inhibitors. Here we show that Metnase interacts with Topo IIα in breast cancer cells, and that reducing Metnase expression significantly increases metaphase decatenation checkpoint arrest. Repression of Metnase sensitizes breast cancer cells to Topo IIα inhibitors, and directly blocks the inhibitory effect of the anthracycline adriamycin on Topo IIα-mediated decatenation in vitro. Thus, Metnase may mediate resistance to Topo IIα inhibitors, and could be a biomarker for clinical sensitivity to anthracyclines. Metnase could also become an important target for combination chemotherapy with current Topo IIα inhibitors, specifically in anthracycline-resistant breast cancer. Public Library of Science 2009-04-24 /pmc/articles/PMC2669129/ /pubmed/19390626 http://dx.doi.org/10.1371/journal.pone.0005323 Text en Wray et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Wray, Justin
Williamson, Elizabeth A.
Royce, Melanie
Shaheen, Montaser
Beck, Brian D.
Lee, Suk-Hee
Nickoloff, Jac A.
Hromas, Robert
Metnase Mediates Resistance to Topoisomerase II Inhibitors in Breast Cancer Cells
title Metnase Mediates Resistance to Topoisomerase II Inhibitors in Breast Cancer Cells
title_full Metnase Mediates Resistance to Topoisomerase II Inhibitors in Breast Cancer Cells
title_fullStr Metnase Mediates Resistance to Topoisomerase II Inhibitors in Breast Cancer Cells
title_full_unstemmed Metnase Mediates Resistance to Topoisomerase II Inhibitors in Breast Cancer Cells
title_short Metnase Mediates Resistance to Topoisomerase II Inhibitors in Breast Cancer Cells
title_sort metnase mediates resistance to topoisomerase ii inhibitors in breast cancer cells
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2669129/
https://www.ncbi.nlm.nih.gov/pubmed/19390626
http://dx.doi.org/10.1371/journal.pone.0005323
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