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Chromatin determinants impart camptothecin sensitivity
Camptothecin‐induced locking of topoisomerase 1 on DNA generates a physical barrier to replication fork progression and creates topological stress. By allowing replisome rotation, absence of the Tof1/Csm3 complex promotes the conversion of impending topological stress to DNA catenation and causes ca...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5452016/ https://www.ncbi.nlm.nih.gov/pubmed/28389464 http://dx.doi.org/10.15252/embr.201643560 |
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author | Puddu, Fabio Salguero, Israel Herzog, Mareike Geisler, Nicola J Costanzo, Vincenzo Jackson, Stephen P |
author_facet | Puddu, Fabio Salguero, Israel Herzog, Mareike Geisler, Nicola J Costanzo, Vincenzo Jackson, Stephen P |
author_sort | Puddu, Fabio |
collection | PubMed |
description | Camptothecin‐induced locking of topoisomerase 1 on DNA generates a physical barrier to replication fork progression and creates topological stress. By allowing replisome rotation, absence of the Tof1/Csm3 complex promotes the conversion of impending topological stress to DNA catenation and causes camptothecin hypersensitivity. Through synthetic viability screening, we discovered that histone H4 K16 deacetylation drives the sensitivity of yeast cells to camptothecin and that inactivation of this pathway by mutating H4 K16 or the genes SIR1‐4 suppresses much of the hypersensitivity of tof1∆ strains towards this agent. We show that disruption of rDNA or telomeric silencing does not mediate camptothecin resistance but that disruption of Sir1‐dependent chromatin domains is sufficient to suppress camptothecin sensitivity in wild‐type and tof1∆ cells. We suggest that topoisomerase 1 inhibition in proximity of these domains causes topological stress that leads to DNA hypercatenation, especially in the absence of the Tof1/Csm3 complex. Finally, we provide evidence of the evolutionarily conservation of this mechanism. |
format | Online Article Text |
id | pubmed-5452016 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-54520162017-06-02 Chromatin determinants impart camptothecin sensitivity Puddu, Fabio Salguero, Israel Herzog, Mareike Geisler, Nicola J Costanzo, Vincenzo Jackson, Stephen P EMBO Rep Articles Camptothecin‐induced locking of topoisomerase 1 on DNA generates a physical barrier to replication fork progression and creates topological stress. By allowing replisome rotation, absence of the Tof1/Csm3 complex promotes the conversion of impending topological stress to DNA catenation and causes camptothecin hypersensitivity. Through synthetic viability screening, we discovered that histone H4 K16 deacetylation drives the sensitivity of yeast cells to camptothecin and that inactivation of this pathway by mutating H4 K16 or the genes SIR1‐4 suppresses much of the hypersensitivity of tof1∆ strains towards this agent. We show that disruption of rDNA or telomeric silencing does not mediate camptothecin resistance but that disruption of Sir1‐dependent chromatin domains is sufficient to suppress camptothecin sensitivity in wild‐type and tof1∆ cells. We suggest that topoisomerase 1 inhibition in proximity of these domains causes topological stress that leads to DNA hypercatenation, especially in the absence of the Tof1/Csm3 complex. Finally, we provide evidence of the evolutionarily conservation of this mechanism. John Wiley and Sons Inc. 2017-04-07 2017-06 /pmc/articles/PMC5452016/ /pubmed/28389464 http://dx.doi.org/10.15252/embr.201643560 Text en © 2017 The Authors. Published under the terms of the CC BY 4.0 license This is an open access article under the terms of the Creative Commons Attribution 4.0 (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 | Articles Puddu, Fabio Salguero, Israel Herzog, Mareike Geisler, Nicola J Costanzo, Vincenzo Jackson, Stephen P Chromatin determinants impart camptothecin sensitivity |
title | Chromatin determinants impart camptothecin sensitivity |
title_full | Chromatin determinants impart camptothecin sensitivity |
title_fullStr | Chromatin determinants impart camptothecin sensitivity |
title_full_unstemmed | Chromatin determinants impart camptothecin sensitivity |
title_short | Chromatin determinants impart camptothecin sensitivity |
title_sort | chromatin determinants impart camptothecin sensitivity |
topic | Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5452016/ https://www.ncbi.nlm.nih.gov/pubmed/28389464 http://dx.doi.org/10.15252/embr.201643560 |
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