Distinct states of nucleolar stress induced by anticancer drugs
Ribosome biogenesis is a vital and highly energy-consuming cellular function occurring primarily in the nucleolus. Cancer cells have an elevated demand for ribosomes to sustain continuous proliferation. This study evaluated the impact of existing anticancer drugs on the nucleolus by screening a libr...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2023-12-01
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| Series: | eLife |
| Subjects: | |
| Online Access: | https://elifesciences.org/articles/88799 |
| _version_ | 1797390117812305920 |
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| author | Tamara A Potapova Jay R Unruh Juliana Conkright-Fincham Charles AS Banks Laurence Florens David Alan Schneider Jennifer L Gerton |
| author_facet | Tamara A Potapova Jay R Unruh Juliana Conkright-Fincham Charles AS Banks Laurence Florens David Alan Schneider Jennifer L Gerton |
| author_sort | Tamara A Potapova |
| collection | DOAJ |
| description | Ribosome biogenesis is a vital and highly energy-consuming cellular function occurring primarily in the nucleolus. Cancer cells have an elevated demand for ribosomes to sustain continuous proliferation. This study evaluated the impact of existing anticancer drugs on the nucleolus by screening a library of anticancer compounds for drugs that induce nucleolar stress. For a readout, a novel parameter termed ‘nucleolar normality score’ was developed that measures the ratio of the fibrillar center and granular component proteins in the nucleolus and nucleoplasm. Multiple classes of drugs were found to induce nucleolar stress, including DNA intercalators, inhibitors of mTOR/PI3K, heat shock proteins, proteasome, and cyclin-dependent kinases (CDKs). Each class of drugs induced morphologically and molecularly distinct states of nucleolar stress accompanied by changes in nucleolar biophysical properties. In-depth characterization focused on the nucleolar stress induced by inhibition of transcriptional CDKs, particularly CDK9, the main CDK that regulates RNA Pol II. Multiple CDK substrates were identified in the nucleolus, including RNA Pol I– recruiting protein Treacle, which was phosphorylated by CDK9 in vitro. These results revealed a concerted regulation of RNA Pol I and Pol II by transcriptional CDKs. Our findings exposed many classes of chemotherapy compounds that are capable of inducing nucleolar stress, and we recommend considering this in anticancer drug development. |
| first_indexed | 2024-03-08T23:07:02Z |
| format | Article |
| id | doaj.art-fc3278bdd9414a3bbee3d9190e4221a8 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-03-08T23:07:02Z |
| publishDate | 2023-12-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-fc3278bdd9414a3bbee3d9190e4221a82023-12-15T13:02:32ZengeLife Sciences Publications LtdeLife2050-084X2023-12-011210.7554/eLife.88799Distinct states of nucleolar stress induced by anticancer drugsTamara A Potapova0https://orcid.org/0000-0003-2761-1795Jay R Unruh1https://orcid.org/0000-0003-3077-4990Juliana Conkright-Fincham2Charles AS Banks3Laurence Florens4https://orcid.org/0000-0002-9310-6650David Alan Schneider5https://orcid.org/0000-0003-0635-5091Jennifer L Gerton6https://orcid.org/0000-0003-0743-3637Stowers Institute for Medical Research, Kansas City, United StatesStowers Institute for Medical Research, Kansas City, United StatesStowers Institute for Medical Research, Kansas City, United StatesStowers Institute for Medical Research, Kansas City, United StatesStowers Institute for Medical Research, Kansas City, United StatesDepartment of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham, United StatesStowers Institute for Medical Research, Kansas City, United States; Department of Biochemistry and Molecular Biology, University of Kansas Medical Center, Kansas City, United StatesRibosome biogenesis is a vital and highly energy-consuming cellular function occurring primarily in the nucleolus. Cancer cells have an elevated demand for ribosomes to sustain continuous proliferation. This study evaluated the impact of existing anticancer drugs on the nucleolus by screening a library of anticancer compounds for drugs that induce nucleolar stress. For a readout, a novel parameter termed ‘nucleolar normality score’ was developed that measures the ratio of the fibrillar center and granular component proteins in the nucleolus and nucleoplasm. Multiple classes of drugs were found to induce nucleolar stress, including DNA intercalators, inhibitors of mTOR/PI3K, heat shock proteins, proteasome, and cyclin-dependent kinases (CDKs). Each class of drugs induced morphologically and molecularly distinct states of nucleolar stress accompanied by changes in nucleolar biophysical properties. In-depth characterization focused on the nucleolar stress induced by inhibition of transcriptional CDKs, particularly CDK9, the main CDK that regulates RNA Pol II. Multiple CDK substrates were identified in the nucleolus, including RNA Pol I– recruiting protein Treacle, which was phosphorylated by CDK9 in vitro. These results revealed a concerted regulation of RNA Pol I and Pol II by transcriptional CDKs. Our findings exposed many classes of chemotherapy compounds that are capable of inducing nucleolar stress, and we recommend considering this in anticancer drug development.https://elifesciences.org/articles/88799nucleolusanticancer drugsRNA Pol ICDK9TCOF1/Treacle |
| spellingShingle | Tamara A Potapova Jay R Unruh Juliana Conkright-Fincham Charles AS Banks Laurence Florens David Alan Schneider Jennifer L Gerton Distinct states of nucleolar stress induced by anticancer drugs eLife nucleolus anticancer drugs RNA Pol I CDK9 TCOF1/Treacle |
| title | Distinct states of nucleolar stress induced by anticancer drugs |
| title_full | Distinct states of nucleolar stress induced by anticancer drugs |
| title_fullStr | Distinct states of nucleolar stress induced by anticancer drugs |
| title_full_unstemmed | Distinct states of nucleolar stress induced by anticancer drugs |
| title_short | Distinct states of nucleolar stress induced by anticancer drugs |
| title_sort | distinct states of nucleolar stress induced by anticancer drugs |
| topic | nucleolus anticancer drugs RNA Pol I CDK9 TCOF1/Treacle |
| url | https://elifesciences.org/articles/88799 |
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