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EBNA1BP2

Probable rRNA-processing protein EBP2 · UniProt Q99848

Length
306 aa
Mass
34.9 kDa
Annotated
2026-06-09
18 papers in source corpus 13 papers cited in narrative 13 extracted findings
Cross-family judge faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

EBNA1BP2 (EBP2) is a nucleolar protein with dual roles in ribosome biogenesis and in tethering Epstein-Barr virus episomes to host chromosomes (PMID:10074103, PMID:22319211). In its conserved cellular function, EBP2 acts as a dynamic, non-static nucleolar scaffold for ribosome assembly (PMID:19170763); yeast genetic and biochemical studies place Ebp2 in early 60S ribosomal subunit assembly, where it cooperates with Brx1 (which depends on Ebp2 for stable pre-ribosome association) and is genetically and physically linked to Mak5, Nop16, Rpf1 and ribosomal proteins Rpl14 and L36/L34/L8, with double mutants showing defective 27S pre-rRNA processing (PMID:22319211, PMID:24312670, PMID:25119672). EBP2 was first identified as a direct binding partner of EBV EBNA1, contacting EBNA1 residues ~325–376, and this interaction is specifically required for stable segregation of oriP episomes—but not transient replication—during cell division (PMID:10074103). EBP2 relocalizes from the nucleolus to the chromosome periphery in mitosis and is required for EBNA1 and EBV plasmids to bind mitotic chromosomes, a step regulated by Aurora B kinase; human EBP2 is essential for cell proliferation and can functionally substitute to rescue episome maintenance in non-permissive murine cells (PMID:15923612, PMID:19887584, PMID:15181471). In cancer contexts, EBP2 binds c-Myc to relocalize it to the nucleolus and block its degradation, forming a positive feedback loop that promotes rRNA synthesis (PMID:24481446); in ALK-positive lymphoma it is tyrosine-phosphorylated by NPM-ALK and suppresses p53 via the Akt–mTORC1 axis (PMID:33040459); and in hepatocellular carcinoma it interacts with CENPA to transcriptionally upregulate MCM8 and HMGB1, promoting homologous recombination DNA repair and tumor progression (PMID:41935051).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 1999 High

    Established why EBV episomes require a host factor for stable inheritance by identifying EBP2 as a direct EBNA1 partner whose binding is necessary specifically for long-term episome maintenance.

    Evidence Yeast two-hybrid/one-hybrid, Co-IP from insect cells, EBNA1 deletion mutagenesis, and long-term plasmid maintenance assay

    PMID:10074103

    Open questions at the time
    • Did not define EBP2's own endogenous cellular function
    • Mechanism by which EBP2 links EBNA1 to chromatin not resolved
  2. 2001 Medium

    Identified EBP2 (as NoBP) as a nucleolar anchor for nuclear FGF3 and a proliferation promoter, providing the first evidence of an endogenous nucleolar role distinct from viral function.

    Evidence Yeast two-hybrid, reciprocal Co-IP, colocalization in COS-1 cells, nuclear/nucleolar targeting signal mapping, overexpression proliferation assay in NIH 3T3

    PMID:11438656

    Open questions at the time
    • Functional significance of FGF3 anchoring in normal physiology unclear
    • Single-lab, overexpression-based proliferation readout
  3. 2004 Medium

    Demonstrated a species-specific functional requirement for human EBP2 by rescuing oriP episome maintenance in murine cells where EBNA1 alone was insufficient.

    Evidence Stable human EBP2 transfection in murine Sp2/0 cells with episomal maintenance assay

    PMID:15181471

    Open questions at the time
    • Molecular basis of species specificity not defined
    • Single functional assay
  4. 2005 High

    Connected EBP2 to mitotic chromosome tethering and cell-cycle control by showing it is essential for proliferation and that Aurora B kinase regulates its chromosome association.

    Evidence siRNA knockdown, small-molecule Aurora B inhibition, yeast ipl1 mutant genetics, fluorescence microscopy across human and yeast systems

    PMID:15923612

    Open questions at the time
    • Whether Aurora B phosphorylates EBP2 directly not established
    • Link between essentiality and ribosome biogenesis not yet made
  5. 2008 Medium

    Characterized EBP2 as a dynamic, mobile nucleolar scaffold for ribosome biogenesis rather than a static structural component.

    Evidence Proteomic nuclear matrix fractionation (HPLC/SDS-PAGE/PMF), FRAP, and RNAi knockdown in HeLa cells

    PMID:19170763

    Open questions at the time
    • Specific ribosome assembly step not pinpointed in human cells
    • Partner proteins not identified
  6. 2009 Medium

    Resolved the spatiotemporal logic of EBP2-EBNA1 cooperation, showing EBP2 relocalizes to the chromosome periphery and contributes to EBNA1-chromosome association in the second half of mitosis.

    Evidence Live-cell fluorescence microscopy and EBNA1 deletion mutant colocalization through mitotic stages

    PMID:19887584

    Open questions at the time
    • Two-stage model not biochemically reconstituted
    • Single-lab imaging study
  7. 2012 High

    Placed Ebp2 mechanistically in early 60S subunit assembly by showing Brx1 requires Ebp2 for stable pre-ribosome association and that the pair is needed for 27S pre-rRNA processing.

    Evidence Synthetic lethal screen, yeast two-hybrid, pre-rRNA processing analysis, and ribosomal subunit fractionation

    PMID:22319211

    Open questions at the time
    • Conservation of this exact assembly role in human cells not directly tested
    • Atomic-level role within pre-60S not defined
  8. 2013 Medium

    Expanded the 60S assembly network by linking Ebp2 genetically to Mak5, Nop16, Rpf1 and Rpl14 and associating it with Nsa1-containing pre-60S particles assembling a eukaryote-specific surface.

    Evidence Synthetic lethal genetic screen, pre-60S particle co-purification, and rix7 overexpression epistasis in yeast

    PMID:24312670

    Open questions at the time
    • Direct physical contacts within the proposed cluster not all resolved
    • Rix7 action on Ebp2-containing particles inferred, not shown directly
  9. 2014 Medium

    Defined direct ribosomal protein contacts (L36, L34, L8) for Ebp2 near the 5.8S rRNA region and tied L36 function to specific pre-rRNA processing steps cooperative with Ebp2.

    Evidence Yeast two-hybrid, multicopy suppressor analysis, synthetic enhancement genetics, and primer-extension pre-rRNA processing assays

    PMID:25119672

    Open questions at the time
    • Structural basis of Ebp2-ribosomal protein binding unknown
    • Human orthologue contacts not validated
  10. 2014 Medium

    Connected EBP2's nucleolar function to oncogenic signaling by showing it binds c-Myc, relocalizes and stabilizes it, and forms a positive feedback loop driving rRNA synthesis and proliferation.

    Evidence Co-IP, colocalization, siRNA knockdown, promoter binding assay, and rRNA synthesis/proliferation readouts

    PMID:24481446

    Open questions at the time
    • FBW7-independent stabilization mechanism not molecularly defined
    • Single-lab study
  11. 2020 Medium

    Implicated EBP2 in lymphoma by showing it is tyrosine-phosphorylated by NPM-ALK and suppresses p53 through the Akt-mTORC1 axis to sustain proliferation.

    Evidence Co-IP, siRNA knockdown, kinase inhibitor treatment, Raptor siRNA epistasis, and flow cytometry cell-cycle analysis in ALCL models

    PMID:33040459

    Open questions at the time
    • Functional consequence of EBP2 tyrosine phosphorylation not defined
    • Direct biochemical link from EBP2 to Akt-mTORC1 not established
  12. 2026 Medium

    Extended EBP2's tumor role to hepatocellular carcinoma via a CENPA interaction that transcriptionally upregulates MCM8 and HMGB1, promoting homologous recombination repair and tumor growth.

    Evidence Co-IP, siRNA knockdown, MCM8 overexpression rescue, in vivo xenograft, and DNA repair assays in HCC cells

    PMID:41935051

    Open questions at the time
    • Mechanism by which an EBP2-CENPA complex drives transcription unclear
    • Direct DNA/promoter binding by EBP2 not shown

Open questions

Synthesis pass · forward-looking unresolved questions
  • Whether EBP2's conserved ribosome biogenesis scaffold function and its various oncogenic/viral chromosome-tethering activities reflect one unified molecular activity or separable interaction surfaces remains unresolved.
  • No structural model of EBP2 bound to any partner
  • No human-cell mapping of the ribosome assembly contacts defined in yeast
  • Whether the same EBP2 domains mediate EBNA1, c-Myc, NPM-ALK and CENPA binding is unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 3 GO:0003723 RNA binding 2
Localization
GO:0005730 nucleolus 5 GO:0005634 nucleus 2 GO:0005694 chromosome 2
Pathway
R-HSA-8953854 Metabolism of RNA 4 R-HSA-1643685 Disease 3 R-HSA-73894 DNA Repair 1
Partners
BRX1CENPAEBNA1FGF3MYCNPM-ALKRPL36A
Complex memberships
pre-60S ribosomal particle

Evidence

Reading pass · 13 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 EBP2 (EBNA1BP2) was identified as a direct binding partner of EBNA1; the interaction was confirmed by yeast two-hybrid, one-hybrid with DNA-bound EBNA1, and co-immunoprecipitation from insect cells. Mapping showed EBP2 binds the region of EBNA1 spanning amino acids ~325–376. EBNA1 mutants lacking this region were defective in EBP2 binding and in long-term oriP plasmid maintenance but not in transient replication, establishing that the EBNA1–EBP2 interaction is specifically required for stable segregation of EBV episomes during cell division. Yeast two-hybrid screen, one-hybrid assay, co-immunoprecipitation from insect cells, EBNA1 deletion mutagenesis, long-term plasmid maintenance assay Journal of virology High 10074103
2005 hEBP2 is essential for human cell proliferation (RNA silencing lethal phenotype) and is required for EBNA1 and EBV-based plasmids to bind mitotic chromosomes. hEBP2 association with mitotic chromatin is cell-cycle regulated and depends on Aurora B kinase (Ipl1 in yeast): RNA silencing or small-molecule inhibition of Aurora B abolished hEBP2 binding to mitotic chromosomes, indicating Aurora B regulates EBP2–chromosome association and thereby EBV segregation. RNA interference (siRNA knockdown), small-molecule Aurora B kinase inhibition, yeast temperature-sensitive mutant analysis (ipl1 mutants), fluorescence microscopy of mitotic chromosome binding Molecular and cellular biology High 15923612
2009 EBP2 localizes to the nucleolus until late prophase, then relocalizes to the chromosome periphery where it remains through telophase. Partial colocalization with EBNA1 occurs from metaphase through telophase. EBNA1 deletion mutagenesis showed the glycine-arginine-rich central region (with minor contribution from N-terminal sequences) mediates chromosome association at each mitotic stage, mirroring the sequence requirements for EBP2 binding, supporting a two-stage model of EBNA1–chromosome interaction in which EBP2 contributes during the second half of mitosis. Live-cell fluorescence microscopy, EBNA1 deletion mutant analysis, colocalization imaging through mitotic stages Journal of cell science Medium 19887584
2001 NoBP (EBNA1BP2) was identified as a nucleolar binding partner of nuclear fibroblast growth factor 3 (FGF3) via yeast two-hybrid; interaction confirmed by co-immunoprecipitation and colocalization in transfected COS-1 cells. The NoBP-binding domain of FGF3 matched the sequence required for FGF3 nucleolar translocation, suggesting NoBP is the nucleolar anchor for FGF3. NoBP overexpression promoted cell proliferation in NIH 3T3 cells and counteracted the growth-inhibitory effect of nuclear FGF3; NoBP contains C-terminal nuclear and nucleolar targeting motifs sufficient to redirect β-galactosidase to the nucleolus. Yeast two-hybrid, co-immunoprecipitation, colocalization imaging, deletion/domain mapping of nuclear targeting signals, overexpression proliferation assay Molecular and cellular biology Medium 11438656
2008 EBNA1BP2 was identified in a ribonucleoprotein-containing nuclear matrix fraction of HeLa cells by proteomics (HPLC/SDS-PAGE/PMF). FRAP and RNAi knockdown analyses demonstrated that EBNA1BP2 functions as a dynamic scaffold component for ribosome biogenesis in the nucleolus, not a static structural element. Proteomic fractionation (HPLC/SDS-PAGE/peptide mass fingerprint), FRAP, RNAi knockdown Genes to cells Medium 19170763
2004 Human EBP2 is specifically required for episomal maintenance of EBV-based oriP vectors: EBNA1 expression alone was insufficient to maintain episomes in murine Sp2/0 cells, but exogenous expression of human EBP2 rescued long-term episomal maintenance, demonstrating the species-specific functional requirement for EBP2 in this process. Stable transfection of human EBP2 in murine Sp2/0 cells, episomal maintenance assay Biochemistry and cell biology Medium 15181471
2012 Yeast Ebp2 functions cooperatively with Brx1 in early steps of 60S ribosomal subunit assembly: synthetic lethality between ebp2-14 and brx1 mutations, two-hybrid interaction between Ebp2 and Brx1, and epistasis experiments showed Brx1 requires Ebp2 for stable association with pre-ribosomes (but not vice versa). Double mutants showed defective 27S pre-rRNA processing and 60S subunit production. Synthetic lethal screen, yeast two-hybrid, pre-rRNA processing analysis (primer extension/Northern), ribosomal subunit fractionation Nucleic acids research High 22319211
2013 Yeast Ebp2 is genetically linked to Mak5, Nop16, and Rpf1 (synthetic lethal interactions) and to ribosomal protein Rpl14 in early pre-60S particle assembly. Ebp2 is associated with Nsa1-containing pre-60S particles. Over-expression of AAA-ATPase Rix7 negatively affects growth of ebp2 mutant cells, suggesting Rix7 may act on structurally defective pre-60S subunits containing Ebp2. The genetic cluster (Mak5, Ebp2, Nop16, Rpf1, Rpl14) is proposed to orchestrate assembly of a eukaryote-specific 60S surface involving Rpl6, Rpl14, Rpl16 and rRNA expansion segments ES7L and ES39L. Synthetic lethal genetic screen, pre-60S particle co-purification, genetic epistasis with rix7 overexpression PloS one Medium 24312670
2014 Yeast Ebp2 two-hybrid analysis showed direct interactions with ribosomal proteins L36a/b, L34a/b, and L8, which in mature ribosomes are located near the 3′ end of 5.8S rRNA. Multicopy RPL36A/B suppressed ebp2 mutant growth defects specifically, and loss of Rpl36a/b caused synthetic enhancement of ebp2-14 growth defects. Pre-rRNA processing analysis showed L36a/b is required for 27SA2, 27SA3, and 27SBL pre-rRNA processing, placing Ebp2 and L36 cooperatively in 60S biogenesis. Yeast two-hybrid, multicopy suppressor analysis, synthetic enhancement genetics, primer extension pre-rRNA processing assay Current genetics Medium 25119672
2014 EBP2 was identified as a direct binding partner of c-Myc in the nucleolus: co-expression of EBP2 relocalized c-Myc from nucleus to nucleolus, while EBP2 depletion reduced nucleolar c-Myc. EBP2 binding blocked c-Myc degradation in an FBW7-independent manner. c-Myc transcriptionally activates EBP2 expression by binding the EBP2 promoter, and EBP2 promotes c-Myc-mediated rRNA synthesis and cell proliferation, forming a positive feedback loop. Co-immunoprecipitation, colocalization imaging, siRNA knockdown, promoter binding assay (ChIP implied), rRNA synthesis assay, cell proliferation assay Cell death & disease Medium 24481446
2020 EBP2 interacts with NPM-ALK in the nucleolus of ALCL cells (interaction dependent on NPM-ALK kinase activity and NPM1-mediated nucleolar localization); NPM-ALK induces tyrosine phosphorylation of EBP2. EBP2 knockdown activated tumor suppressor p53, causing G0/G1 arrest in NPM-ALK-transformed Ba/F3 and Ki-JK cells; this p53 activation was suppressed by Akt inhibition, mTORC1 inhibition (rapamycin), or Raptor knockdown, placing EBP2 upstream of the Akt–mTORC1–p53 axis. Co-immunoprecipitation, siRNA knockdown, kinase inhibitor treatment, Raptor siRNA epistasis, flow cytometry cell cycle analysis Molecular oncology Medium 33040459
2008 Ectopic overexpression of EBP2-EGFP in HEK293 stable clones elevated cyclin E1 mRNA and protein levels, increased p21 expression, and induced ATM (Ser1981) and p53 (Ser15) phosphorylation, yet did not increase Cdk2 kinase activity. After prolonged passage, EBP2-overexpressing clones showed chromosomal instability (loss of 4–5 chromosomes per cell), linking deregulated EBP2 expression to cell cycle dysregulation. Stable EBP2-EGFP overexpression, RT-PCR, Western blot, flow cytometry, kinase activity assay, cytogenetic analysis BMB reports Low 18959818
2026 EBP2 interacts with CENPA in HCC cells and through this interaction transcriptionally upregulates MCM8, stabilizing the MCM8/MCM9 complex and enhancing homologous recombination-mediated DNA repair. In parallel, EBP2 regulates HMGB1 expression via a CENPA/YY1 transcriptional complex. Functional rescue experiments showed MCM8 overexpression abrogated suppressive effects of EBP2 knockdown on HCC cell proliferation and migration. Co-immunoprecipitation (EBP2–CENPA interaction), siRNA knockdown, overexpression rescue, in vivo xenograft, DNA repair assay Cell death & disease Medium 41935051

Source papers

Stage 0 corpus · 18 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1999 EBP2, a human protein that interacts with sequences of the Epstein-Barr virus nuclear antigen 1 important for plasmid maintenance. Journal of virology 139 10074103
2005 EBP2 plays a key role in Epstein-Barr virus mitotic segregation and is regulated by aurora family kinases. Molecular and cellular biology 65 15923612
2002 A novel Plasmodium falciparum erythrocyte binding protein-2 (EBP2/BAEBL) involved in erythrocyte receptor binding. Molecular and biochemical parasitology 63 11814568
2001 EBP2 is a member of the yeast RRB regulon, a transcriptionally coregulated set of genes that are required for ribosome and rRNA biosynthesis. Molecular and cellular biology 58 11713296
2009 Mitotic chromosome interactions of Epstein-Barr nuclear antigen 1 (EBNA1) and human EBNA1-binding protein 2 (EBP2). Journal of cell science 43 19887584
2014 A positive feedback loop between EBP2 and c-Myc regulates rDNA transcription, cell proliferation, and tumorigenesis. Cell death & disease 35 24481446
2012 Ebp2 and Brx1 function cooperatively in 60S ribosomal subunit assembly in Saccharomyces cerevisiae. Nucleic acids research 33 22319211
2013 Mak5 and Ebp2 act together on early pre-60S particles and their reduced functionality bypasses the requirement for the essential pre-60S factor Nsa1. PloS one 30 24312670
2001 NoBP, a nuclear fibroblast growth factor 3 binding protein, is cell cycle regulated and promotes cell growth. Molecular and cellular biology 27 11438656
2008 Proteomic and targeted analytical identification of BXDC1 and EBNA1BP2 as dynamic scaffold proteins in the nucleolus. Genes to cells : devoted to molecular & cellular mechanisms 20 19170763
2014 Roles of Ebp2 and ribosomal protein L36 in ribosome biogenesis in Saccharomyces cerevisiae. Current genetics 16 25119672
2020 EBP2, a novel NPM-ALK-interacting protein in the nucleolus, contributes to the proliferation of ALCL cells by regulating tumor suppressor p53. Molecular oncology 7 33040459
2008 Ectopic EBP2 expression enhances cyclin E1 expression and induces chromosome instability in HEK293 stable clones. BMB reports 5 18959818
2022 Antibody response to a new member of the DBL family (EBP2) after a brief Plasmodium vivax exposure. PLoS neglected tropical diseases 4 35714097
2024 Natural genetic diversity of the DBL domain of a novel member of the Plasmodium vivax erythrocyte binding-like proteins (EBP2) in the Amazon rainforest. Infection, genetics and evolution : journal of molecular epidemiology and evolutionary genetics in infectious diseases 3 38936525
2004 Maintenance of Epstein-Barr virus-derived episomal vectors in the murine Sp2/0 myeloma cell line is dependent upon exogenous expression of human EBP2. Biochemistry and cell biology = Biochimie et biologie cellulaire 2 15181471
2026 EBNA1BP2 (EBP2) promotes the progression of hepatocellular carcinoma through upregulating the expression of MCM8 and HMGB1. Cell death & disease 0 41935051
2023 Domain definition and preliminary functional exploration of the endonuclease NOBP-1 in Strongyloides stercoralis. Parasites & vectors 0 37924155

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