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Genome-Wide Transcriptional Effects of the Anti-Cancer Agent Camptothecin
The anti-cancer drug camptothecin inhibits replication and transcription by trapping DNA topoisomerase I (Top1) covalently to DNA in a “cleavable complex”. To examine the effects of camptothecin on RNA synthesis genome-wide we used Bru-Seq and show that camptothecin treatment primarily affected tran...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2013
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3806802/ https://www.ncbi.nlm.nih.gov/pubmed/24194914 http://dx.doi.org/10.1371/journal.pone.0078190 |
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author | Veloso, Artur Biewen, Benjamin Paulsen, Michelle T. Berg, Nathan Carmo de Andrade Lima, Leonardo Prasad, Jayendra Bedi, Karan Magnuson, Brian Wilson, Thomas E. Ljungman, Mats |
author_facet | Veloso, Artur Biewen, Benjamin Paulsen, Michelle T. Berg, Nathan Carmo de Andrade Lima, Leonardo Prasad, Jayendra Bedi, Karan Magnuson, Brian Wilson, Thomas E. Ljungman, Mats |
author_sort | Veloso, Artur |
collection | PubMed |
description | The anti-cancer drug camptothecin inhibits replication and transcription by trapping DNA topoisomerase I (Top1) covalently to DNA in a “cleavable complex”. To examine the effects of camptothecin on RNA synthesis genome-wide we used Bru-Seq and show that camptothecin treatment primarily affected transcription elongation. We also observed that camptothecin increased RNA reads past transcription termination sites as well as at enhancer elements. Following removal of camptothecin, transcription spread as a wave from the 5’-end of genes with no recovery of transcription apparent from RNA polymerases stalled in the body of genes. As a result, camptothecin preferentially inhibited the expression of large genes such as proto-oncogenes, and anti-apoptotic genes while smaller ribosomal protein genes, pro-apoptotic genes and p53 target genes showed relative higher expression. Cockayne syndrome group B fibroblasts (CS-B), which are defective in transcription-coupled repair (TCR), showed an RNA synthesis recovery profile similar to normal fibroblasts suggesting that TCR is not involved in the repair of or RNA synthesis recovery from transcription-blocking Top1 lesions. These findings of the effects of camptothecin on transcription have important implications for its anti-cancer activities and may aid in the design of improved combinatorial treatments involving Top1 poisons. |
format | Online Article Text |
id | pubmed-3806802 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-38068022013-11-05 Genome-Wide Transcriptional Effects of the Anti-Cancer Agent Camptothecin Veloso, Artur Biewen, Benjamin Paulsen, Michelle T. Berg, Nathan Carmo de Andrade Lima, Leonardo Prasad, Jayendra Bedi, Karan Magnuson, Brian Wilson, Thomas E. Ljungman, Mats PLoS One Research Article The anti-cancer drug camptothecin inhibits replication and transcription by trapping DNA topoisomerase I (Top1) covalently to DNA in a “cleavable complex”. To examine the effects of camptothecin on RNA synthesis genome-wide we used Bru-Seq and show that camptothecin treatment primarily affected transcription elongation. We also observed that camptothecin increased RNA reads past transcription termination sites as well as at enhancer elements. Following removal of camptothecin, transcription spread as a wave from the 5’-end of genes with no recovery of transcription apparent from RNA polymerases stalled in the body of genes. As a result, camptothecin preferentially inhibited the expression of large genes such as proto-oncogenes, and anti-apoptotic genes while smaller ribosomal protein genes, pro-apoptotic genes and p53 target genes showed relative higher expression. Cockayne syndrome group B fibroblasts (CS-B), which are defective in transcription-coupled repair (TCR), showed an RNA synthesis recovery profile similar to normal fibroblasts suggesting that TCR is not involved in the repair of or RNA synthesis recovery from transcription-blocking Top1 lesions. These findings of the effects of camptothecin on transcription have important implications for its anti-cancer activities and may aid in the design of improved combinatorial treatments involving Top1 poisons. Public Library of Science 2013-10-23 /pmc/articles/PMC3806802/ /pubmed/24194914 http://dx.doi.org/10.1371/journal.pone.0078190 Text en © 2013 Veloso 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 Veloso, Artur Biewen, Benjamin Paulsen, Michelle T. Berg, Nathan Carmo de Andrade Lima, Leonardo Prasad, Jayendra Bedi, Karan Magnuson, Brian Wilson, Thomas E. Ljungman, Mats Genome-Wide Transcriptional Effects of the Anti-Cancer Agent Camptothecin |
title | Genome-Wide Transcriptional Effects of the Anti-Cancer Agent Camptothecin |
title_full | Genome-Wide Transcriptional Effects of the Anti-Cancer Agent Camptothecin |
title_fullStr | Genome-Wide Transcriptional Effects of the Anti-Cancer Agent Camptothecin |
title_full_unstemmed | Genome-Wide Transcriptional Effects of the Anti-Cancer Agent Camptothecin |
title_short | Genome-Wide Transcriptional Effects of the Anti-Cancer Agent Camptothecin |
title_sort | genome-wide transcriptional effects of the anti-cancer agent camptothecin |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3806802/ https://www.ncbi.nlm.nih.gov/pubmed/24194914 http://dx.doi.org/10.1371/journal.pone.0078190 |
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