Affinage

BRPF3

Bromodomain and PHD finger-containing protein 3 · UniProt Q9ULD4

Round 2 corrected
Length
1205 aa
Mass
135.7 kDa
Annotated
2026-04-28
45 papers in source corpus 9 papers cited in narrative 9 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

BRPF3 is a multivalent chromatin reader and scaffolding subunit that preferentially partners with the HBO1 (KAT7/MYST2) histone acetyltransferase to form a tetrameric complex with ING4/5 and EAF6, directing site-specific histone H3K14 acetylation at replication origins near transcription start sites to promote CDC45 loading and efficient origin firing during S phase (PMID:26620551, PMID:26677226). Its bromodomain selectively reads mono-acetylated H4K5ac and di-acetylated H4K5acK12ac marks, providing a chromatin-targeting mechanism for HBO1 complex recruitment (PMID:34448544). Beyond scaffolding enzymatic activity, BRPF3 stabilizes HBO1 protein by antagonizing HUWE1-mediated ubiquitin-proteasomal degradation, and dysregulation of this axis perturbs cell-cycle progression and lineage commitment in embryonic stem cells (PMID:32555450). In cardiac fibroblasts, circ-CELF1 stabilizes BRPF3 to scaffold KAT7-dependent H3K14 acetylation at the Celf1 promoter, establishing a profibrotic feedback loop (PMID:41132846).

Mechanistic history

Synthesis pass · year-by-year structured walk · 7 steps
  1. 2006 Medium

    Identification of BRPF3 as a component of ING5-containing HAT complexes linked BRPF-family proteins to DNA replication origin function through association with the MCM helicase, raising the question of which specific acetyltransferase BRPF3 partners with and how this regulates replication.

    Evidence Protein purification, co-immunoprecipitation, and RNAi knockdown with S-phase replication assays in human cells

    PMID:16387653

    Open questions at the time
    • BRPF3 not individually distinguished from BRPF1/BRPF2 in complex
    • direct BRPF3–MCM interaction not tested
  2. 2008 High

    Reconstitution experiments established that BRPF-family proteins (including BRPF3) serve as scaffolding subunits bridging MOZ/MORF catalytic subunits to ING5 and EAF6, and that complex formation dramatically stimulates nucleosomal acetyltransferase activity, defining the architectural role of BRPFs in MYST complexes.

    Evidence Reconstitution of tetrameric complexes, deletion mapping, and in vitro acetyltransferase assays

    PMID:18794358

    Open questions at the time
    • BRPF3 specificity for HBO1 versus MOZ/MORF not resolved in this study
    • in vivo chromatin substrate preference not addressed
  3. 2015 High

    Two concurrent studies resolved BRPF3's partner selectivity and genomic function: BRPF3 preferentially assembles with HBO1 (not MOZ, MORF, TIP60, or MOF), this complex acetylates H3K14 specifically, and genome-wide profiling showed BRPF3/HBO1/H3K14ac co-occupy replication origins near TSSs; BRPF3 depletion impairs CDC45 loading without affecting MCM helicase recruitment, pinpointing its role in origin activation rather than pre-RC assembly.

    Evidence Reciprocal endogenous co-IP, Brpf3-knockout mouse, ChIP-seq, RNAi screen with CDC45/MCM chromatin loading assays

    PMID:26620551 PMID:26677226

    Open questions at the time
    • Mechanism by which H3K14ac facilitates CDC45 recruitment remains undefined
    • Brpf3-null mice are viable, so compensatory mechanisms are uncharacterized
    • contribution of other BRPF-family members at shared origins not excluded
  4. 2020 High

    Beyond scaffolding, BRPF3 was shown to stabilize HBO1 protein by directly antagonizing HUWE1-mediated ubiquitination and proteasomal degradation, revealing a post-translational regulatory axis; overexpression of BRPF3 in mouse ESCs aberrantly upregulated HBO1, dysregulated cell-cycle progression, and impaired lineage commitment during embryoid body differentiation.

    Evidence Co-immunoprecipitation, in vivo ubiquitination assays, BRPF3 overexpression/knockdown in mouse ESCs, rescue by HUWE1 overexpression, embryoid body differentiation assays

    PMID:32555450

    Open questions at the time
    • Structural basis of BRPF3–HUWE1 competition for HBO1 binding unknown
    • whether BRPF3 stabilization of HBO1 is relevant at replication origins specifically not tested
  5. 2021 Medium

    Biochemical characterization of the BRPF3 bromodomain revealed selective recognition of H4K5ac and H4K5acK12ac, establishing how BRPF3 reads pre-existing histone acetylation marks to recruit the HBO1 complex to chromatin.

    Evidence Fluorescence-based binding assays with acetylated histone peptides, pulldown on purified human histones, molecular dynamics simulations

    PMID:34448544

    Open questions at the time
    • In vivo contribution of bromodomain reader activity versus PHD fingers to chromatin targeting not dissected by mutagenesis in cells
    • whether H4K5ac recognition is required for origin-specific localization untested
  6. 2023 Medium

    Functional dissection in ovarian carcinoma cells showed that BRPF3 knockdown or bromodomain inhibition sensitizes cells to PARP inhibitors, while HBO1 catalytic inhibition does not, suggesting a reader-dependent, HAT-independent role of BRPF3 in DNA damage tolerance or repair.

    Evidence siRNA knockdown, pharmacological inhibition of BRPF3 and HBO1, PARPi resistance assays, histone mass spectrometry, RNA-seq

    PMID:37493106

    Open questions at the time
    • Downstream pathway linking BRPF3 bromodomain to PARPi resistance not identified
    • whether BRPF3 directly participates in DNA repair or acts indirectly through transcriptional regulation unclear
  7. 2025 Medium

    A circ-CELF1/BRPF3/KAT7 feedback loop was defined in cardiac fibroblasts: circ-CELF1 stabilizes BRPF3 by reducing its ubiquitination, BRPF3 scaffolds KAT7 to acetylate H3K14 at the Celf1 promoter, and resulting CELF1 expression suppresses Smad7 to drive fibrosis, extending BRPF3's scaffolding function to a pathological transcriptional context.

    Evidence CircRNA overexpression/knockdown, co-IP, ChIP for H3K14ac at Celf1 promoter, ubiquitination assays, cardiac fibroblast functional assays

    PMID:41132846

    Open questions at the time
    • Single-laboratory finding not yet independently confirmed
    • identity of the E3 ligase targeting BRPF3 in fibroblasts (whether HUWE1 or another) not determined

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include how H3K14ac deposited by the BRPF3–HBO1 complex mechanistically facilitates CDC45 loading at origins, whether the bromodomain reader and HAT-scaffolding functions are separable in vivo, and the structural basis for BRPF3's selectivity for HBO1 over other MYST-family acetyltransferases.
  • No high-resolution structure of the BRPF3–HBO1 interface
  • Mechanism coupling H3K14ac to CMG helicase activation undefined
  • Bromodomain versus PHD-finger contributions to in vivo chromatin targeting not genetically separated

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 3 GO:0042393 histone binding 1 GO:0140110 transcription regulator activity 1
Localization
GO:0005634 nucleus 2 GO:0000228 nuclear chromosome 1
Pathway
R-HSA-4839726 Chromatin organization 4 R-HSA-69306 DNA Replication 2 R-HSA-74160 Gene expression (Transcription) 1
Partners
EAF6HUWE1ING4ING5KAT6AKAT6BKAT7
Complex memberships
HBO1–BRPF3–ING5–EAF6MOZ/MORF–BRPF3–ING5–EAF6

Evidence

Reading pass · 9 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2008 BRPF3 (along with BRPF1 and BRPF2) acts as a scaffolding subunit in tetrameric MOZ/MORF histone acetyltransferase complexes, bridging the association of MOZ/MORF catalytic subunits with ING5 and EAF6. Complex formation with BRPF proteins dramatically stimulates acetyltransferase activity toward nucleosomal histone H3 and free histones H3 and H4. Reconstitution of complexes, deletion mapping, in vitro acetyltransferase assays, co-immunoprecipitation Molecular and cellular biology High 18794358
2006 BRPF3 (as part of HBO1 and MOZ/MORF complexes) is associated with ING5, which is essential for DNA replication during S phase. ING5-containing HAT complexes interact with the MCM helicase, linking these complexes to replication origin function. Protein purification, co-immunoprecipitation, RNAi knockdown with S-phase replication assays Molecular cell Medium 16387653
2015 BRPF3 forms a specific tetrameric complex preferentially with HBO1 (KAT7/MYST2) but not with related acetyltransferases MOZ, MORF, TIP60, or MOF. This complex specifically acetylates histone H3K14. BRPF3 is dispensable for mouse development and survival, distinguishing it from BRPF1 and BRPF2. Co-immunoprecipitation of endogenous complexes, RT-qPCR, lacZ reporter mouse strain, Brpf3 knockout mouse analysis The Journal of biological chemistry High 26677226
2015 BRPF3 forms a complex with HBO1 that specifically acetylates histone H3K14. Genome-wide analysis shows BRPF3, HBO1, and H3K14ac are enriched at ORC1-binding sites and replication origins near transcription start sites (TSSs). BRPF3 is required for H3K14ac at selected origins and for efficient replication origin activation; CDC45 recruitment (but not MCM2-7 loading) is impaired upon BRPF3 depletion. RNAi screen measuring RPA accumulation under replication stress, ChIP-seq, co-immunoprecipitation, CDC45/MCM chromatin loading assays The EMBO journal High 26620551
2021 The BRPF3 bromodomain specifically recognizes mono-acetylated H4K5ac and di-acetylated H4K5acK12ac histone peptides. Pull-down assays on purified histones from human cells confirmed the interaction of BRPF3 bromodomain with acetylated histone H4. MD simulations defined the binding mode of acetyllysine within the bromodomain. Fluorescence-based binding assays with acetylated histone peptides, pulldown assays on purified human histones, molecular dynamics simulations Chemistry, an Asian journal Medium 34448544
2020 BRPF3 protein level is critical for the stability of MYST2 (HBO1/KAT7). The E3 ubiquitin ligase HUWE1 ubiquitinates MYST2 and targets it for proteasomal degradation, while BRPF3 antagonizes this degradation through direct protein-protein interaction with MYST2. BRPF3 overexpression causes aberrant upregulation of MYST2, leading to dysregulated cell-cycle progression and delayed embryoid body formation and lineage commitment in mouse ESCs; these effects are reversed by HUWE1 overexpression. Co-immunoprecipitation, ubiquitination assays, overexpression and knockdown in mouse ESCs, embryoid body differentiation assays, cell-cycle analysis Cell death and differentiation High 32555450
2023 Knockdown and pharmacological inhibition of BRPF3 reduces PARP inhibitor (olaparib) resistance in high-grade serous ovarian carcinoma cells, whereas pharmacologic inhibition of HBO1 (which depletes H3K14ac) does not affect PARPi response. This suggests BRPF3's bromodomain reader function, rather than HAT catalytic activity, plays a more direct role in PARPi resistance. siRNA knockdown, pharmacological inhibition, PARPi resistance assays, mass spectrometry histone modification profiling, RNA-seq Molecular carcinogenesis Medium 37493106
2025 In cardiac fibroblasts, the circular RNA circ-CELF1 reduces ubiquitination-mediated degradation of BRPF3, elevating BRPF3 protein levels. Elevated BRPF3 then acts as a scaffold to recruit histone acetyltransferase KAT7, facilitating H3K14 acetylation at the Celf1 gene promoter and activating Celf1 transcription, which suppresses downstream Smad7 expression to promote cardiac fibrosis. This establishes a feedback loop: CELF1/circ-CELF1/BRPF3/KAT7. CircRNA overexpression/knockdown, co-immunoprecipitation, ChIP assay for H3K14ac at Celf1 promoter, ubiquitination assays, cardiac fibroblast functional assays Acta pharmaceutica Sinica. B Medium 41132846
2016 KAT7 (HBO1/MYST2), the acetyltransferase that partners with BRPF3, interacts with centromere assembly factor M18BP1 and is required for centromeric CENP-A assembly. Loss of KAT7 leads to chromosome misalignment and micronuclei formation. Tethering KAT7 to ectopic alphoid DNA removes H3K9me3 and stimulates new CENP-A assembly, demonstrating KAT7-containing complexes (of which BRPF3 is a subunit) support centromere chromatin competence. KAT7 knockout in HeLa cells, co-immunoprecipitation with M18BP1, ChIP, artificial chromosome tethering assays, immunofluorescence Developmental cell Low 27270040

Source papers

Stage 0 corpus · 45 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2015 A human interactome in three quantitative dimensions organized by stoichiometries and abundances. Cell 1015 26496610
2020 A reference map of the human binary protein interactome. Nature 849 32296183
2018 VIRMA mediates preferential m6A mRNA methylation in 3'UTR and near stop codon and associates with alternative polyadenylation. Cell discovery 829 29507755
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2003 Characterization of the proteins released from activated platelets leads to localization of novel platelet proteins in human atherosclerotic lesions. Blood 616 14630798
2006 ING tumor suppressor proteins are critical regulators of chromatin acetylation required for genome expression and perpetuation. Molecular cell 550 16387653
2022 OpenCell: Endogenous tagging for the cartography of human cellular organization. Science (New York, N.Y.) 432 35271311
2021 A proximity-dependent biotinylation map of a human cell. Nature 339 34079125
2003 The DNA sequence and analysis of human chromosome 6. Nature 242 14574404
2015 Screen identifies bromodomain protein ZMYND8 in chromatin recognition of transcription-associated DNA damage that promotes homologous recombination. Genes & development 203 25593309
2008 Molecular architecture of quartet MOZ/MORF histone acetyltransferase complexes. Molecular and cellular biology 193 18794358
2011 The Hbo1-Brd1/Brpf2 complex is responsible for global acetylation of H3K14 and required for fetal liver erythropoiesis. Blood 172 21753189
2009 Ubiquitin-mediated proteolysis of HuR by heat shock. The EMBO journal 142 19322201
2015 BRPF3-HBO1 regulates replication origin activation and histone H3K14 acetylation. The EMBO journal 113 26620551
1999 Prediction of the coding sequences of unidentified human genes. XV. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro. DNA research : an international journal for rapid publication of reports on genes and genomes 111 10574462
2019 Systematic bromodomain protein screens identify homologous recombination and R-loop suppression pathways involved in genome integrity. Genes & development 110 31753913
2015 MOZ and MORF acetyltransferases: Molecular interaction, animal development and human disease. Biochimica et biophysica acta 107 25920810
2018 Histone Interaction Landscapes Visualized by Crosslinking Mass Spectrometry in Intact Cell Nuclei. Molecular & cellular proteomics : MCP 101 30021884
2022 EZH2 depletion potentiates MYC degradation inhibiting neuroblastoma and small cell carcinoma tumor formation. Nature communications 99 35013218
2020 Systematic mapping of genetic interactions for de novo fatty acid synthesis identifies C12orf49 as a regulator of lipid metabolism. Nature metabolism 92 32694731
1981 Characterization of the proteins of isolated human platelet alpha-granules. Evidence for a separate alpha-granule-pool of the glycoproteins IIb and IIIa. Biochimica et biophysica acta 83 6457647
2014 Human-chromatin-related protein interactions identify a demethylase complex required for chromosome segregation. Cell reports 80 24981860
2020 Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains. Cell reports 79 32814053
2016 KAT7/HBO1/MYST2 Regulates CENP-A Chromatin Assembly by Antagonizing Suv39h1-Mediated Centromere Inactivation. Developmental cell 79 27270040
2014 1,3-Dimethyl Benzimidazolones Are Potent, Selective Inhibitors of the BRPF1 Bromodomain. ACS medicinal chemistry letters 71 25408830
2017 Biological function and histone recognition of family IV bromodomain-containing proteins. Journal of cellular physiology 66 28500727
2007 Systematic identification of SH3 domain-mediated human protein-protein interactions by peptide array target screening. Proteomics 66 17474147
2016 GSK6853, a Chemical Probe for Inhibition of the BRPF1 Bromodomain. ACS medicinal chemistry letters 57 27326325
2017 Benzoisoquinolinediones as Potent and Selective Inhibitors of BRPF2 and TAF1/TAF1L Bromodomains. Journal of medicinal chemistry 47 28402630
2017 Histone-binding of DPF2 mediates its repressive role in myeloid differentiation. Proceedings of the National Academy of Sciences of the United States of America 36 28533407
2015 The Chromatin Regulator BRPF3 Preferentially Activates the HBO1 Acetyltransferase but Is Dispensable for Mouse Development and Survival. The Journal of biological chemistry 34 26677226
2024 Identifying therapeutic target genes for migraine by systematic druggable genome-wide Mendelian randomization. The journal of headache and pain 24 38867170
2023 Sequential genome-wide CRISPR-Cas9 screens identify genes regulating cell-surface expression of tetraspanins. Cell reports 20 36724073
2020 BRPF3-HUWE1-mediated regulation of MYST2 is required for differentiation and cell-cycle progression in embryonic stem cells. Cell death and differentiation 13 32555450
2020 A functionally defined high-density NRF2 interactome reveals new conditional regulators of ARE transactivation. Redox biology 13 32911434
2020 Genetic Markers for Later Remission in Response to Early Improvement of Antidepressants. International journal of molecular sciences 12 32664413
2021 Insights into the Molecular Mechanisms of Histone Code Recognition by the BRPF3 Bromodomain. Chemistry, an Asian journal 11 34448544
2023 Targeting BRPF3 moderately reverses olaparib resistance in high grade serous ovarian carcinoma. Molecular carcinogenesis 4 37493106
2025 Human protein interaction networks of ancestral and variant SARS-CoV-2 in organ-specific cells and bodily fluids. Nature communications 2 40593736
2025 A novel feedback loop: CELF1/circ-CELF1/BRPF3/KAT7 in cardiac fibrosis. Acta pharmaceutica Sinica. B 2 41132846
2025 Highly Efficient Site-Specific and Cassette Mutagenesis of Plasmids Harboring GC-Rich Sequences. Cells 2 41440036
2025 Identification of m6A-modified gene signatures in lung adenocarcinoma tumorigenesis and their potential role in drug resistance. Discover oncology 1 40131660