Defective RNA polymerase III is negatively regulated by the SUMO-ubiquitin-Cdc48 pathway

Zheng Wang; Catherine Wu; Aaron Aslanian; John R. Yates; Tony Hunter

doi:10.7554/eLife.35447

Defective RNA polymerase III is negatively regulated by the SUMO-ubiquitin-Cdc48 pathway

Zheng Wang, Catherine Wu, Aaron Aslanian, John R. Yates, Tony Hunter

Research output: Contribution to journal › Article › peer-review

19 Scopus citations

Abstract

Transcription by RNA polymerase III (Pol III) is an essential cellular process, and mutations in Pol III can cause neurodegenerative disease in humans. However, in contrast to Pol II transcription, which has been extensively studied, the knowledge of how Pol III is regulated is very limited. We report here that in budding yeast, Saccharomyces cerevisiae, Pol III is negatively regulated by the Small Ubiquitin-like MOdifier (SUMO), an essential post-translational modification pathway. Besides sumoylation, Pol III is also targeted by ubiquitylation and the Cdc48/p97 segregase; these three processes likely act in a sequential manner and eventually lead to proteasomal degradation of Pol III subunits, thereby repressing Pol III transcription. This study not only uncovered a regulatory mechanism for Pol III, but also suggests that the SUMO and ubiquitin modification pathways and the Cdc48/p97 segregase can be potential therapeutic targets for Pol III-related human diseases.

Original language	English (US)
Article number	e35447
Journal	eLife
Volume	7
DOIs	https://doi.org/10.7554/eLife.35447
State	Published - Sep 2018
Externally published	Yes

ASJC Scopus subject areas

Neuroscience(all)
Immunology and Microbiology(all)
Biochemistry, Genetics and Molecular Biology(all)

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.7554/eLife.35447

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@article{b8c86fbdafb54ab5a4e17dd89110d94b,

title = "Defective RNA polymerase III is negatively regulated by the SUMO-ubiquitin-Cdc48 pathway",

abstract = "Transcription by RNA polymerase III (Pol III) is an essential cellular process, and mutations in Pol III can cause neurodegenerative disease in humans. However, in contrast to Pol II transcription, which has been extensively studied, the knowledge of how Pol III is regulated is very limited. We report here that in budding yeast, Saccharomyces cerevisiae, Pol III is negatively regulated by the Small Ubiquitin-like MOdifier (SUMO), an essential post-translational modification pathway. Besides sumoylation, Pol III is also targeted by ubiquitylation and the Cdc48/p97 segregase; these three processes likely act in a sequential manner and eventually lead to proteasomal degradation of Pol III subunits, thereby repressing Pol III transcription. This study not only uncovered a regulatory mechanism for Pol III, but also suggests that the SUMO and ubiquitin modification pathways and the Cdc48/p97 segregase can be potential therapeutic targets for Pol III-related human diseases.",

author = "Zheng Wang and Catherine Wu and Aaron Aslanian and Yates, {John R.} and Tony Hunter",

note = "Funding Information: We thank Gregory Prelich for the SUMO pathway mutant plasmids and strains and the wild type genomic DNA library, Martin Kupiec for the ade3-pink plasmid, Michel Werner for the rpc160 and rpc31 mutant plasmids, Vicki Lundblad for sharing yeast vectors and equipment, and Jill Meisen-helder for the 2x Flag peptide. We also thank James Moresco and Jolene Diedrich for technical support on TMT-M/S analysis, Benoit Coulombe and Genevieve Bernard for sharing unpublished data on Pol III-related diseases, as well as Ian Willis, Alessandro Vannini, Gregory Prelich, and members of the Hunter lab for constructive discussions. This study was supported by NIH grants #CA080100, CA082683 and CA014195 to TH, NCRR grant #5P41RR011823-17 and NIGMS grant #8P41GM103533-17 to JRY, the Helmsley Center for Genomic Medicine, the Functional Genomics Core, and the Mass Spectrometry Core of the Salk Institute with funding from NIH-NCI CCSG: P30 014195. TH holds the Renato Dulbecco Chair in Cancer Research, and is a Frank and Else Schilling American Cancer Society Professor. Publisher Copyright: {\textcopyright} Wang et al.",

year = "2018",

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AU - Wang, Zheng

AU - Wu, Catherine

AU - Aslanian, Aaron

AU - Yates, John R.

AU - Hunter, Tony

N1 - Funding Information: We thank Gregory Prelich for the SUMO pathway mutant plasmids and strains and the wild type genomic DNA library, Martin Kupiec for the ade3-pink plasmid, Michel Werner for the rpc160 and rpc31 mutant plasmids, Vicki Lundblad for sharing yeast vectors and equipment, and Jill Meisen-helder for the 2x Flag peptide. We also thank James Moresco and Jolene Diedrich for technical support on TMT-M/S analysis, Benoit Coulombe and Genevieve Bernard for sharing unpublished data on Pol III-related diseases, as well as Ian Willis, Alessandro Vannini, Gregory Prelich, and members of the Hunter lab for constructive discussions. This study was supported by NIH grants #CA080100, CA082683 and CA014195 to TH, NCRR grant #5P41RR011823-17 and NIGMS grant #8P41GM103533-17 to JRY, the Helmsley Center for Genomic Medicine, the Functional Genomics Core, and the Mass Spectrometry Core of the Salk Institute with funding from NIH-NCI CCSG: P30 014195. TH holds the Renato Dulbecco Chair in Cancer Research, and is a Frank and Else Schilling American Cancer Society Professor. Publisher Copyright: © Wang et al.

PY - 2018/9

Y1 - 2018/9

N2 - Transcription by RNA polymerase III (Pol III) is an essential cellular process, and mutations in Pol III can cause neurodegenerative disease in humans. However, in contrast to Pol II transcription, which has been extensively studied, the knowledge of how Pol III is regulated is very limited. We report here that in budding yeast, Saccharomyces cerevisiae, Pol III is negatively regulated by the Small Ubiquitin-like MOdifier (SUMO), an essential post-translational modification pathway. Besides sumoylation, Pol III is also targeted by ubiquitylation and the Cdc48/p97 segregase; these three processes likely act in a sequential manner and eventually lead to proteasomal degradation of Pol III subunits, thereby repressing Pol III transcription. This study not only uncovered a regulatory mechanism for Pol III, but also suggests that the SUMO and ubiquitin modification pathways and the Cdc48/p97 segregase can be potential therapeutic targets for Pol III-related human diseases.

AB - Transcription by RNA polymerase III (Pol III) is an essential cellular process, and mutations in Pol III can cause neurodegenerative disease in humans. However, in contrast to Pol II transcription, which has been extensively studied, the knowledge of how Pol III is regulated is very limited. We report here that in budding yeast, Saccharomyces cerevisiae, Pol III is negatively regulated by the Small Ubiquitin-like MOdifier (SUMO), an essential post-translational modification pathway. Besides sumoylation, Pol III is also targeted by ubiquitylation and the Cdc48/p97 segregase; these three processes likely act in a sequential manner and eventually lead to proteasomal degradation of Pol III subunits, thereby repressing Pol III transcription. This study not only uncovered a regulatory mechanism for Pol III, but also suggests that the SUMO and ubiquitin modification pathways and the Cdc48/p97 segregase can be potential therapeutic targets for Pol III-related human diseases.

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Defective RNA polymerase III is negatively regulated by the SUMO-ubiquitin-Cdc48 pathway

Abstract

ASJC Scopus subject areas

UN SDGs

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