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  Nascent-protein ubiquitination is required for heat shock-induced gene downregulation in human cells

Aprile-Garcia, F., Parul, T., Hummel, B., Khavaran, A., & Sawarkar, R. (2019). Nascent-protein ubiquitination is required for heat shock-induced gene downregulation in human cells. Nature Structural and Molecular Biology, 137-146. doi:10.1038/s41594-018-0182-x.

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Item Permalink: http://hdl.handle.net/21.11116/0000-0004-6842-D Version Permalink: http://hdl.handle.net/21.11116/0000-0004-D901-6
Genre: Journal Article

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 Creators:
Aprile-Garcia, Fernando1, Author
Parul, Tomar1, Author
Hummel, Barbara1, Author
Khavaran, Ashkan1, 2, Author
Sawarkar, Ritwick1, Author              
Affiliations:
1Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society, 79108 Freiburg, DE, ou_2243640              
2External Organizations, ou_persistent22              

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 Abstract: Proteotoxic stress such as heat shock causes heat-shock factor (HSF)-dependent transcriptional upregulation of chaperones. Heat shock also leads to a rapid and reversible downregulation of many genes, a process we term stress-induced transcriptional attenuation (SITA). The mechanism underlying this conserved phenomenon is unknown. Here we report that enhanced recruitment of negative transcription elongation factors to gene promoters in human cell lines induces SITA. A chemical inhibitor screen showed that active translation and protein ubiquitination are required for the response. We further find that proteins translated during heat shock are subjected to ubiquitination and that p38 kinase signaling connects cytosolic translation with gene downregulation. Notably, brain samples of subjects with Huntington's disease also show transcriptional attenuation, which is recapitulated in cellular models of protein aggregation similar to heat shock. Thus our work identifies an HSF-independent mechanism that links nascent-protein ubiquitination to transcriptional downregulation during heat shock, with potential ramifications in neurodegenerative diseases.

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Language(s): eng - English
 Dates: 2019-02
 Publication Status: Published in print
 Pages: -
 Publishing info: -
 Table of Contents: -
 Rev. Method: Peer
 Identifiers: DOI: 10.1038/s41594-018-0182-x
 Degree: -

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Title: Nature Structural and Molecular Biology
  Other : Nature Struct Biol
Source Genre: Journal
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Publ. Info: New York, NY : Nature Pub. Group
Pages: - Volume / Issue: - Sequence Number: - Start / End Page: 137 - 146 Identifier: ISSN: 1545-9993
CoNE: https://pure.mpg.de/cone/journals/resource/954925603763