Camptothecin resistance is determined by the regulation of topoisomerase I degradation mediated by ubiquitin proteasome pathway
Proteasomal degradation of topoisomerase I (topoI) is one of the most remarkable cellular phenomena observed in response to camptothecin (CPT). Importantly, the rate of topoI degradation is linked to CPT resistance. Formation of the topoI-DNA-CPT cleavable complex inhibits DNA re-ligation resulting...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | en_US |
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Impact Journals/National Center for Biotechnology Information (U.S.)
2017
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| Online Access: | http://hdl.handle.net/1721.1/109949 https://orcid.org/0000-0002-1545-1651 |
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| author | Ando, Koji Shah, Ankur K. Sachdev, Vibhu Kleinstiver, Benjamin P. Taylor-Parker, Julian Welch, Moira M. Hu, Yiheng Salgia, Ravi Parvin, Jeffrey D. Ozonoff, Al Rameh, Lucia E. Joung, J. Keith Bharti, Ajit K. White, Forest M. |
| author2 | Massachusetts Institute of Technology. Department of Biological Engineering |
| author_facet | Massachusetts Institute of Technology. Department of Biological Engineering Ando, Koji Shah, Ankur K. Sachdev, Vibhu Kleinstiver, Benjamin P. Taylor-Parker, Julian Welch, Moira M. Hu, Yiheng Salgia, Ravi Parvin, Jeffrey D. Ozonoff, Al Rameh, Lucia E. Joung, J. Keith Bharti, Ajit K. White, Forest M. |
| author_sort | Ando, Koji |
| collection | MIT |
| description | Proteasomal degradation of topoisomerase I (topoI) is one of the most remarkable cellular phenomena observed in response to camptothecin (CPT). Importantly, the rate of topoI degradation is linked to CPT resistance. Formation of the topoI-DNA-CPT cleavable complex inhibits DNA re-ligation resulting in DNA-double strand break (DSB). The degradation of topoI marks the first step in the ubiquitin proteasome pathway (UPP) dependent DNA damage response (DDR). Here, we show that the Ku70/Ku80 heterodimer binds with topoI, and that the DNA-dependent protein kinase (DNA-PKcs) phosphorylates topoI on serine 10 (topoI-pS10), which is subsequently ubiquitinated by BRCA1. A higher basal level of topoI-pS10 ensures rapid topoI degradation leading to CPT resistance. Importantly, PTEN regulates DNA-PKcs kinase activity in this pathway and PTEN deletion ensures DNA-PKcs dependent higher topoI-pS10, rapid topoI degradation and CPT resistance. |
| first_indexed | 2024-09-23T17:03:41Z |
| format | Article |
| id | mit-1721.1/109949 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T17:03:41Z |
| publishDate | 2017 |
| publisher | Impact Journals/National Center for Biotechnology Information (U.S.) |
| record_format | dspace |
| spelling | mit-1721.1/1099492022-10-03T10:08:08Z Camptothecin resistance is determined by the regulation of topoisomerase I degradation mediated by ubiquitin proteasome pathway Ando, Koji Shah, Ankur K. Sachdev, Vibhu Kleinstiver, Benjamin P. Taylor-Parker, Julian Welch, Moira M. Hu, Yiheng Salgia, Ravi Parvin, Jeffrey D. Ozonoff, Al Rameh, Lucia E. Joung, J. Keith Bharti, Ajit K. White, Forest M. Massachusetts Institute of Technology. Department of Biological Engineering Koch Institute for Integrative Cancer Research at MIT White, Forest M Proteasomal degradation of topoisomerase I (topoI) is one of the most remarkable cellular phenomena observed in response to camptothecin (CPT). Importantly, the rate of topoI degradation is linked to CPT resistance. Formation of the topoI-DNA-CPT cleavable complex inhibits DNA re-ligation resulting in DNA-double strand break (DSB). The degradation of topoI marks the first step in the ubiquitin proteasome pathway (UPP) dependent DNA damage response (DDR). Here, we show that the Ku70/Ku80 heterodimer binds with topoI, and that the DNA-dependent protein kinase (DNA-PKcs) phosphorylates topoI on serine 10 (topoI-pS10), which is subsequently ubiquitinated by BRCA1. A higher basal level of topoI-pS10 ensures rapid topoI degradation leading to CPT resistance. Importantly, PTEN regulates DNA-PKcs kinase activity in this pathway and PTEN deletion ensures DNA-PKcs dependent higher topoI-pS10, rapid topoI degradation and CPT resistance. 2017-06-16T15:15:36Z 2017-06-16T15:15:36Z 2017-03 2017-02 Article http://purl.org/eprint/type/JournalArticle 1949-2553 http://hdl.handle.net/1721.1/109949 Ando, Koji; Shah, Ankur K.; Sachdev, Vibhu; Kleinstiver, Benjamin P.; Taylor-Parker, Julian; Welch, Moira M.; Hu, Yiheng et al. “Camptothecin Resistance Is Determined by the Regulation of Topoisomerase I Degradation Mediated by Ubiquitin Proteasome Pathway.” Oncotarget (November 2015): 16376 https://orcid.org/0000-0002-1545-1651 en_US http://dx.doi.org/10.18632/oncotarget.16376 Oncotarget Creative Commons Attribution 3.0 Unported license http://creativecommons.org/licenses/by/3.0/ application/pdf Impact Journals/National Center for Biotechnology Information (U.S.) Impact Journals |
| spellingShingle | Ando, Koji Shah, Ankur K. Sachdev, Vibhu Kleinstiver, Benjamin P. Taylor-Parker, Julian Welch, Moira M. Hu, Yiheng Salgia, Ravi Parvin, Jeffrey D. Ozonoff, Al Rameh, Lucia E. Joung, J. Keith Bharti, Ajit K. White, Forest M. Camptothecin resistance is determined by the regulation of topoisomerase I degradation mediated by ubiquitin proteasome pathway |
| title | Camptothecin resistance is determined by the regulation of topoisomerase I degradation mediated by ubiquitin proteasome pathway |
| title_full | Camptothecin resistance is determined by the regulation of topoisomerase I degradation mediated by ubiquitin proteasome pathway |
| title_fullStr | Camptothecin resistance is determined by the regulation of topoisomerase I degradation mediated by ubiquitin proteasome pathway |
| title_full_unstemmed | Camptothecin resistance is determined by the regulation of topoisomerase I degradation mediated by ubiquitin proteasome pathway |
| title_short | Camptothecin resistance is determined by the regulation of topoisomerase I degradation mediated by ubiquitin proteasome pathway |
| title_sort | camptothecin resistance is determined by the regulation of topoisomerase i degradation mediated by ubiquitin proteasome pathway |
| url | http://hdl.handle.net/1721.1/109949 https://orcid.org/0000-0002-1545-1651 |
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