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Oncogenes induce genotoxic stress by mitotic processing of unusual replication intermediates
Oncogene-induced DNA replication stress activates the DNA damage response (DDR), a crucial anticancer barrier. DDR inactivation in these conditions promotes genome instability and tumor progression, but the underlying molecular mechanisms are elusive. We found that overexpression of both Cyclin E an...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The Rockefeller University Press
2013
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3601361/ https://www.ncbi.nlm.nih.gov/pubmed/23479741 http://dx.doi.org/10.1083/jcb.201212058 |
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author | Neelsen, Kai J. Zanini, Isabella M.Y. Herrador, Raquel Lopes, Massimo |
author_facet | Neelsen, Kai J. Zanini, Isabella M.Y. Herrador, Raquel Lopes, Massimo |
author_sort | Neelsen, Kai J. |
collection | PubMed |
description | Oncogene-induced DNA replication stress activates the DNA damage response (DDR), a crucial anticancer barrier. DDR inactivation in these conditions promotes genome instability and tumor progression, but the underlying molecular mechanisms are elusive. We found that overexpression of both Cyclin E and Cdc25A rapidly slowed down replication forks and induced fork reversal, suggestive of increased topological stress. Surprisingly, these phenotypes, per se, are neither associated with chromosomal breakage nor with significant DDR activation. Oncogene-induced DNA breakage and DDR activation instead occurred upon persistent G2/M arrest or, in a checkpoint-defective context, upon premature CDK1 activation. Depletion of MUS81, a cell cycle–regulated nuclease, markedly limited chromosomal breakage and led to further accumulation of reversed forks. We propose that nucleolytic processing of unusual replication intermediates mediates oncogene-induced genotoxicity and that limiting such processing to mitosis is a central anti-tumorigenic function of the DNA damage checkpoints. |
format | Online Article Text |
id | pubmed-3601361 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
publisher | The Rockefeller University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-36013612013-09-18 Oncogenes induce genotoxic stress by mitotic processing of unusual replication intermediates Neelsen, Kai J. Zanini, Isabella M.Y. Herrador, Raquel Lopes, Massimo J Cell Biol Research Articles Oncogene-induced DNA replication stress activates the DNA damage response (DDR), a crucial anticancer barrier. DDR inactivation in these conditions promotes genome instability and tumor progression, but the underlying molecular mechanisms are elusive. We found that overexpression of both Cyclin E and Cdc25A rapidly slowed down replication forks and induced fork reversal, suggestive of increased topological stress. Surprisingly, these phenotypes, per se, are neither associated with chromosomal breakage nor with significant DDR activation. Oncogene-induced DNA breakage and DDR activation instead occurred upon persistent G2/M arrest or, in a checkpoint-defective context, upon premature CDK1 activation. Depletion of MUS81, a cell cycle–regulated nuclease, markedly limited chromosomal breakage and led to further accumulation of reversed forks. We propose that nucleolytic processing of unusual replication intermediates mediates oncogene-induced genotoxicity and that limiting such processing to mitosis is a central anti-tumorigenic function of the DNA damage checkpoints. The Rockefeller University Press 2013-03-18 /pmc/articles/PMC3601361/ /pubmed/23479741 http://dx.doi.org/10.1083/jcb.201212058 Text en © 2013 Neelsen et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/). |
spellingShingle | Research Articles Neelsen, Kai J. Zanini, Isabella M.Y. Herrador, Raquel Lopes, Massimo Oncogenes induce genotoxic stress by mitotic processing of unusual replication intermediates |
title | Oncogenes induce genotoxic stress by mitotic processing of unusual replication intermediates |
title_full | Oncogenes induce genotoxic stress by mitotic processing of unusual replication intermediates |
title_fullStr | Oncogenes induce genotoxic stress by mitotic processing of unusual replication intermediates |
title_full_unstemmed | Oncogenes induce genotoxic stress by mitotic processing of unusual replication intermediates |
title_short | Oncogenes induce genotoxic stress by mitotic processing of unusual replication intermediates |
title_sort | oncogenes induce genotoxic stress by mitotic processing of unusual replication intermediates |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3601361/ https://www.ncbi.nlm.nih.gov/pubmed/23479741 http://dx.doi.org/10.1083/jcb.201212058 |
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