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  The bromodomain protein BRD4 regulates splicing during heat shock

Hussong, M., Kaehler, C., Kerick, M., Grimm, C., Franz, A., Timmermann, B., et al. (2017). The bromodomain protein BRD4 regulates splicing during heat shock. Nucleic Acids Research (London), 45(1), 382-394. doi:10.1093/nar/gkw729.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-002B-53BC-B Version Permalink: http://hdl.handle.net/21.11116/0000-0000-FDCC-E
Genre: Journal Article

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© The Author(s) 2016. Published by Oxford University Press on behalf of Nucleic Acids Research.

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 Creators:
Hussong, Michelle1, Author              
Kaehler, Christian2, Author              
Kerick, Martin, Author
Grimm, Christina, Author
Franz, Alexander, Author
Timmermann, Bernd3, Author              
Welzel, Franziska4, Author              
Isensee, Jörg, Author
Hucho, Tim, Author
Krobitsch, Sylvia2, Author              
Schweiger, Michal R.1, Author              
Affiliations:
1Cancer Genomics (Michal-Ruth Schweiger), Dept. of Vertebrate Genomics (Head: Hans Lehrach), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1479649              
2Neurodegenerative Disorders (Sylvia Krobitsch), Independent Junior Research Groups (OWL), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1479661              
3Sequencing (Head: Bernd Timmermann), Scientific Service (Head: Christoph Krukenkamp), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1479670              
4Dept. of Vertebrate Genomics (Head: Hans Lehrach), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1433550              

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 Abstract: The cellular response to heat stress is an ancient and evolutionarily highly conserved defence mechanism characterised by the transcriptional up-regulation of cyto-protective genes and a partial inhibition of splicing. These features closely resemble the proteotoxic stress response during tumor development. The bromodomain protein BRD4 has been identified as an integral member of the oxidative stress as well as of the inflammatory response, mainly due to its role in the transcriptional regulation process. In addition, there are also several lines of evidence implicating BRD4 in the splicing process. Using RNA-sequencing we found a significant increase in splicing inhibition, in particular intron retentions (IR), following heat treatment in BRD4-depleted cells. This leads to a decrease of mRNA abundancy of the affected transcripts, most likely due to premature termination codons. Subsequent experiments revealed that BRD4 interacts with the heat shock factor 1 (HSF1) such that under heat stress BRD4 is recruited to nuclear stress bodies and non-coding SatIII RNA transcripts are up-regulated. These findings implicate BRD4 as an important regulator of splicing during heat stress. Our data which links BRD4 to the stress induced splicing process may provide novel mechanisms of BRD4 inhibitors in regard to anti-cancer therapies.

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Language(s): eng - English
 Dates: 2016-08-102016-08-172017-01-09
 Publication Status: Published in print
 Pages: 13
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 Identifiers: DOI: 10.1093/nar/gkw729
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Title: Nucleic Acids Research (London)
  Other : Nucleic Acids Res
Source Genre: Journal
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Publ. Info: Oxford : Oxford University Press
Pages: - Volume / Issue: 45 (1) Sequence Number: - Start / End Page: 382 - 394 Identifier: ISSN: 0305-1048
CoNE: https://pure.mpg.de/cone/journals/resource/110992357379342