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

Erber, Luke; Luo, Ang; Chen, Yue

doi:10.1074/mcp.ra119.001535

Cited by 21 publications

(23 citation statements)

References 53 publications

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“…Finally, the less well-characterized post-translational modifications of BRD4 include proline hydroxylation and isomerization. Prolyl hydroxylase domain protein PHD2 is the key regulatory enzyme of BRD4 proline hydroxylation (P536) that significantly influences BRD4 interaction with CDK9, CDK1, and MCM5 and affects BRD4 transcriptional activation, but not BRD4 degradation or abundance (Erber et al, 2019). Prolyl isomerase PIN1 regulates the stability and transcriptional activity and oncogenic potential of BRD4 in gastric cancer cells.…”

Section: Modulation Of Bromodomain and Extra-terminal Domain Protein Functions By Post-translational Modificationsmentioning

confidence: 99%

The Functions of BET Proteins in Gene Transcription of Biology and Diseases

Cheung

Kim

Zhou

2021

Front. Mol. Biosci.

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The BET (bromodomain and extra-terminal domain) family proteins, consisting of BRD2, BRD3, BRD4, and testis-specific BRDT, are widely acknowledged as major transcriptional regulators in biology. They are characterized by two tandem bromodomains (BDs) that bind to lysine-acetylated histones and transcription factors, recruit transcription factors and coactivators to target gene sites, and activate RNA polymerase II machinery for transcriptional elongation. Pharmacological inhibition of BET proteins with BD inhibitors has been shown as a promising therapeutic strategy for the treatment of many human diseases including cancer and inflammatory disorders. The recent advances in bromodomain protein biology have further uncovered the complex and versatile functions of BET proteins in the regulation of gene expression in chromatin. In this review article, we highlight our current understanding of BET proteins’ functions in mediating protein–protein interactions required for chromatin-templated gene transcription and splicing, chromatin remodeling, DNA replication, and DNA damage repair. We further discuss context-dependent activator vs. repressor functions of individual BET proteins, isoforms, and bromodomains that may be harnessed for future development of BET bromodomain inhibitors as emerging epigenetic therapies for cancer and inflammatory disorders.

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Section: Modulation Of Bromodomain and Extra-terminal Domain Protein Functions By Post-translational Modificationsmentioning

confidence: 99%

The Functions of BET Proteins in Gene Transcription of Biology and Diseases

Cheung

Kim

Zhou

2021

Front. Mol. Biosci.

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“…This hydroxylation does not destabilize BRD4, but regulates gene transcription by controlling the interaction between BRD4 and other transcription activators, such as the pTEFb complex. [42] In addition, long noncoding RNA NEAT1 binds BRD4 and restrains its activity. [43]…”

Section: The Regulators Of Brd4mentioning

confidence: 99%

BRD4 in physiology and pathology: ‘‘BET’’ on its partners

Liang

Tian

2021

BioEssays

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Bromodomain-containing 4 (BRD4), a member of Bromo and Extra-Terminal (BET) family, recognizes acetylated histones and is of importance in transcription, replication, and DNA repair. It also binds non-histone proteins, DNA and RNA, contributing to development, tissue growth, and various physiological processes. Additionally, BRD4 has been implicated in driving diverse diseases, ranging from cancer, viral infection, inflammation to neurological disorders. Inhibiting its functions with BET inhibitors (BETis) suppresses the progression of several types of cancer, creating an impetus for translating these chemicals to the clinic. The diverse roles of BRD4 are largely dependent on its interaction partners in different contexts. In this review we discuss the molecular mechanisms of BRD4 with its interacting partners in physiology and pathology. Current development of BETis is also summarized. Further understanding the functions of BRD4 and its partners will facilitate resolving the liabilities of present BETis and accelerate their clinical translation.

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“…To evaluate the site-specific prevalence of proline hydroxylation, a stoichiometry-based quantification strategy was integrated into the analysis workflow using the previously established principles [8d, 14]. Briefly, the Hyp stoichiometry was calculated by dividing the summed intensities of the peptides with the Hyp site identification with the total intensities of the peptides containing the same proline site in the dataset.…”

Section: Resultsmentioning

confidence: 99%

“…We collected MS data from the human proteome draft [23], deep proteome analysis of human cell lines [24], PHD interactome analysis [14, 25] and Hyp proteome analysis [8d] as well as IP-MS analysis of Flag-tagged HIF1A. All MS raw data collected above were searched with MaxQuant (version 1.5.3.12) against the Uniprot human database while having carbamidomethyl cystine as fixed modification and protein N-terminal acetylation, methionine oxidation, and proline hydroxylation as variable modification.…”

Section: Experimental Methodsmentioning

confidence: 99%

Deep Proteome Profiling Enabled Functional Annotation and Data-Independent Quantification of Proline Hydroxylation Targets

Gong

Behera

Erber

et al. 2022

Preprint

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Proline hydroxylation (Hyp) regulates protein structure, stability and protein-protein interaction and is widely involved in diverse metabolic and physiological pathways in cells and diseases. To reveal functional features of the proline hydroxylation proteome, we integrated various data sources for deep proteome profiling of proline hydroxylation proteome in human and developed HypDB (https://www.HypDB.site), an annotated database and web server for proline hydroxylation proteome. HypDB provides site-specific evidence of modification based on extensive LC-MS analysis and literature mining with 15319 non-redundant Hyp sites and 8226 sites with high confidence on human proteins. Annotation analysis revealed significant enrichment of proline hydroxylation on key functional domains and tissue-specific distribution of Hyp abundance across 26 types of human organs and fluids and 6 cell lines. The network connectivity analysis further revealed a critical role of proline hydroxylation in mediating protein-protein interactions. Moreover, the spectral library generated by HypDB enabled data-independent analysis (DIA) of clinical tissues and the identification of novel Hyp biomarkers in lung cancer and kidney cancer. Taken together, our integrated analysis of human proteome with publicly accessible HypDB revealed functional diversity of Hyp substrates and provides a quantitative data source to characterize proline hydroxylation in pathways and diseases.

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

Cited by 21 publications

References 53 publications

The Functions of BET Proteins in Gene Transcription of Biology and Diseases

The Functions of BET Proteins in Gene Transcription of Biology and Diseases

BRD4 in physiology and pathology: ‘‘BET’’ on its partners

Deep Proteome Profiling Enabled Functional Annotation and Data-Independent Quantification of Proline Hydroxylation Targets

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