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Molecular & Cellular Proteomics

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Targeted and Interactome Proteomics Revealed the Role of PHD2 in Regulating BRD4 Proline Hydroxylation

Luke Erber, Ang Luo and Yue Chen  Correspondence email
Molecular & Cellular Proteomics September 1, 2019, First published on June 25, 2019, 18 (9) 1772-1781; https://doi.org/10.1074/mcp.RA119.001535
Luke Erber
Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN 55455
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Ang Luo
Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN 55455
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Yue Chen
Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN 55455
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  • For correspondence: YueChen@umn.edu
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Graphical Abstract

Figure1
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Highlights

  • BRD4 interaction with prolyl hydroxylase domain proteins.

  • Stoichiometric dynamics and site-specific regulation of BRD4 proline hydroxylation.

  • BRD4 interactome analysis in response to prolyl hydroxylase activity.

  • Proline hydroxylation pathway regulation of BRD4-mediated transcriptional activity.

Abstract

Proline hydroxylation is a critical cellular mechanism regulating energy homeostasis and development. Our previous study identified and validated Bromodomain-containing protein 4 (BRD4) as a proline hydroxylation substrate in cancer cells. Yet, the regulatory mechanism and the functional significance of the modification remain unknown. In this study, we developed targeted quantification assays using parallel-reaction monitoring and biochemical analysis to identify the major regulatory enzyme of BRD4 proline hydroxylation. We further performed quantitative interactome analysis to determine the functional significance of the modification pathway in BRD4-mediated protein-protein interactions and gene transcription. Our findings revealed that PHD2 is the key regulatory enzyme of BRD4 proline hydroxylation and the modification significantly affects BRD4 interactions with key transcription factors as well as BRD4-mediated transcriptional activation. Taken together, this study provided mechanistic insights into the oxygen-dependent modification of BRD4 and revealed new roles of the pathway in regulating BRD4-dependent gene expression.

  • Omics
  • Affinity proteomics
  • Label-free quantification
  • Post-translational modifications*
  • Transcription*
  • BRD4
  • oxygen sensing
  • PHD2
  • proline hydroxylation

Footnotes

  • Author contributions: L.N.E. and A.L. performed research; L.N.E. and A.L. analyzed data; L.N.E. and Y.C. wrote the paper; Y.C. designed research.

  • ↵* This work was supported by the University of Minnesota research start-up fund (to Y.C.) and the National Institute of Health (1R35GM124896 to Y.C.).

  • ↵Embedded Image This article contains supplemental material.

  • Received April 30, 2019.
  • Revision received June 19, 2019.
  • © 2019 Erber et al.

Published under exclusive license by The American Society for Biochemistry and Molecular Biology, Inc.

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Targeted and Interactome Proteomics Revealed the Role of PHD2 in Regulating BRD4 Proline Hydroxylation
Luke Erber, Ang Luo, Yue Chen
Molecular & Cellular Proteomics September 1, 2019, First published on June 25, 2019, 18 (9) 1772-1781; DOI: 10.1074/mcp.RA119.001535

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Targeted and Interactome Proteomics Revealed the Role of PHD2 in Regulating BRD4 Proline Hydroxylation
Luke Erber, Ang Luo, Yue Chen
Molecular & Cellular Proteomics September 1, 2019, First published on June 25, 2019, 18 (9) 1772-1781; DOI: 10.1074/mcp.RA119.001535
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Molecular & Cellular Proteomics: 18 (9)
Molecular & Cellular Proteomics
Vol. 18, Issue 9
1 Sep 2019
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