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

Luke Erber1, Ang Luo1, Yue Chen1

  • 1Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN 55455.

Molecular & Cellular Proteomics : MCP
|June 27, 2019
PubMed

Insights

This study identifies Prolyl Hydroxylase Domain 2 (PHD2) as the key enzyme regulating Bromodomain-containing protein 4 (BRD4) proline hydroxylation. This oxygen-dependent modification impacts BRD4 interactions and gene transcription.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cancer Research

Background:

  • Proline hydroxylation is crucial for cellular energy and development.
  • Bromodomain-containing protein 4 (BRD4) was previously identified as a proline hydroxylation substrate in cancer cells.
  • The regulatory mechanisms and functional roles of BRD4 proline hydroxylation were previously unknown.

Purpose of the Study:

  • To identify the primary enzyme regulating BRD4 proline hydroxylation.
  • To elucidate the functional significance of BRD4 proline hydroxylation in protein-protein interactions and gene transcription.
  • To provide mechanistic insights into oxygen-dependent BRD4 modification.

Main Methods:

  • Development of targeted quantification assays using parallel-reaction monitoring.
  • Biochemical analysis to identify the key regulatory enzyme.
  • Quantitative interactome analysis to assess functional significance.

Main Results:

  • Prolyl Hydroxylase Domain 2 (PHD2) was identified as the key regulatory enzyme for BRD4 proline hydroxylation.
  • BRD4 proline hydroxylation significantly impacts its interactions with key transcription factors.
  • The modification affects BRD4-mediated transcriptional activation and gene expression.

Conclusions:

  • PHD2 is the critical enzyme controlling BRD4 proline hydroxylation.
  • BRD4 proline hydroxylation plays a significant role in regulating BRD4-mediated gene transcription.
  • This study reveals new functions for oxygen-dependent modification pathways in controlling BRD4 activity.
Keywords:
Affinity proteomicsBRD4Label-free quantificationOmicsPHD2Post-translational modifications*Transcription*oxygen sensingproline hydroxylation

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