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The NELF pausing checkpoint mediates the functional divergence of Cdk9
Promoter-proximal pausing by RNA Pol II is a rate-determining step in gene transcription that is hypothesized to be a prominent point at which regulatory factors act. The pausing factor NELF is known to induce and stabilize pausing, but not all kinds of pausing are NELF-mediated. Here, we find that...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10182999/ https://www.ncbi.nlm.nih.gov/pubmed/37179384 http://dx.doi.org/10.1038/s41467-023-38359-y |
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author | DeBerardine, Michael Booth, Gregory T. Versluis, Philip P. Lis, John T. |
author_facet | DeBerardine, Michael Booth, Gregory T. Versluis, Philip P. Lis, John T. |
author_sort | DeBerardine, Michael |
collection | PubMed |
description | Promoter-proximal pausing by RNA Pol II is a rate-determining step in gene transcription that is hypothesized to be a prominent point at which regulatory factors act. The pausing factor NELF is known to induce and stabilize pausing, but not all kinds of pausing are NELF-mediated. Here, we find that NELF-depleted Drosophila melanogaster cells functionally recapitulate the NELF-independent pausing we previously observed in fission yeast (which lack NELF). Critically, only NELF-mediated pausing establishes a strict requirement for Cdk9 kinase activity for the release of paused Pol II into productive elongation. Upon inhibition of Cdk9, cells with NELF efficiently shutdown gene transcription, while in NELF-depleted cells, defective, non-productive transcription continues unabated. By introducing a strict checkpoint for Cdk9, the evolution of NELF was likely critical to enable increased regulation of Cdk9 in higher eukaryotes, as Cdk9 availability can be restricted to limit gene transcription without inducing wasteful, non-productive transcription. |
format | Online Article Text |
id | pubmed-10182999 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-101829992023-05-15 The NELF pausing checkpoint mediates the functional divergence of Cdk9 DeBerardine, Michael Booth, Gregory T. Versluis, Philip P. Lis, John T. Nat Commun Article Promoter-proximal pausing by RNA Pol II is a rate-determining step in gene transcription that is hypothesized to be a prominent point at which regulatory factors act. The pausing factor NELF is known to induce and stabilize pausing, but not all kinds of pausing are NELF-mediated. Here, we find that NELF-depleted Drosophila melanogaster cells functionally recapitulate the NELF-independent pausing we previously observed in fission yeast (which lack NELF). Critically, only NELF-mediated pausing establishes a strict requirement for Cdk9 kinase activity for the release of paused Pol II into productive elongation. Upon inhibition of Cdk9, cells with NELF efficiently shutdown gene transcription, while in NELF-depleted cells, defective, non-productive transcription continues unabated. By introducing a strict checkpoint for Cdk9, the evolution of NELF was likely critical to enable increased regulation of Cdk9 in higher eukaryotes, as Cdk9 availability can be restricted to limit gene transcription without inducing wasteful, non-productive transcription. Nature Publishing Group UK 2023-05-13 /pmc/articles/PMC10182999/ /pubmed/37179384 http://dx.doi.org/10.1038/s41467-023-38359-y Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article DeBerardine, Michael Booth, Gregory T. Versluis, Philip P. Lis, John T. The NELF pausing checkpoint mediates the functional divergence of Cdk9 |
title | The NELF pausing checkpoint mediates the functional divergence of Cdk9 |
title_full | The NELF pausing checkpoint mediates the functional divergence of Cdk9 |
title_fullStr | The NELF pausing checkpoint mediates the functional divergence of Cdk9 |
title_full_unstemmed | The NELF pausing checkpoint mediates the functional divergence of Cdk9 |
title_short | The NELF pausing checkpoint mediates the functional divergence of Cdk9 |
title_sort | nelf pausing checkpoint mediates the functional divergence of cdk9 |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10182999/ https://www.ncbi.nlm.nih.gov/pubmed/37179384 http://dx.doi.org/10.1038/s41467-023-38359-y |
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