Affinage

BAZ2A

Bromodomain adjacent to zinc finger domain protein 2A · UniProt Q9UIF9

Length
1905 aa
Mass
211.2 kDa
Annotated
2026-06-09
23 papers in source corpus 13 papers cited in narrative 13 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

BAZ2A (TIP5) is a multi-domain chromatin reader-scaffold that recruits the nucleolar remodeling machinery to genomic loci to enforce transcriptional repression and heterochromatin organization (PMID:25533489, PMID:33433018). It engages chromatin through distinct modules: a PHD finger that reads unmodified H3 tails and a bromodomain that recognizes acetylated histones via a KacXXR motif, with both modules cooperating in trans-histone recognition required for recruitment and rDNA repression (PMID:25533489). The bromodomain specifically binds H3K14ac (deposited by EP300) at inactive enhancers, and disrupting this interaction by point mutation or small-molecule inhibition impairs prostate cancer stem cell features and Pten-loss-driven transformation (PMID:34403195). Its TAM domain adopts an MBD-like fold that binds double-stranded DNA and RNA in a sequence-nonspecific, backbone-dependent manner, and also serves as the nucleolar localization and nuclear matrix targeting module that drives large-scale rDNA chromatin compaction (PMID:25916849, PMID:34715126, PMID:23580549). Through these interactions BAZ2A partners with SNF2H, TOP2A, cohesin and KDM1A to constrain chromatin accessibility at repressive (B) compartments and to silence enhancer-controlled genes via an RNA-dependent mechanism distinct from rDNA silencing (PMID:33433018, PMID:37184661). BAZ2A additionally maintains repressive epigenetic states with EZH2 in metastasis-related genes and is required for the initiation of Pten-loss prostate oncogenesis (PMID:25485837, PMID:32024754).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 2013 Medium

    Defined which BAZ2A module anchors rDNA chromatin to the nuclear scaffold, addressing how the complex organizes large-scale rDNA architecture.

    Evidence Domain deletion/mutation, nuclear fractionation, and DNase I accessibility assays on overexpressed Tip5

    PMID:23580549

    Open questions at the time
    • Performed under overexpression conditions
    • Does not resolve TAM-domain ligand specificity for matrix association
  2. 2013 Medium

    Identified an upstream regulator of TIP5 expression, showing NuRD limits TIP5 levels to keep rDNA promoters unmethylated.

    Evidence ChIP at the TIP5 promoter plus knockdown of NuRD components measuring TIP5 expression and rDNA methylation

    PMID:23796711

    Open questions at the time
    • Single lab
    • Direct DNA methyltransferase recruitment by TIP5 not structurally defined
  3. 2014 Medium

    Established a cancer-relevant repressive partnership by showing BAZ2A interacts with EZH2 to silence metastasis-suppressed genes.

    Evidence Co-immunoprecipitation with supporting genomic occupancy data in prostate cancer cells

    PMID:25485837

    Open questions at the time
    • Single Co-IP without reciprocal validation reported
    • Direct vs. complex-mediated interaction not separated
  4. 2014 High

    Defined the structural basis for histone-tail reading, showing the PHD finger and bromodomain act as cooperating modules for chromatin recruitment.

    Evidence X-ray crystallography of PHD and bromodomain in free and histone-bound forms plus SAXS of the combined module

    PMID:25533489

    Open questions at the time
    • In vivo combinatorial readout at endogenous loci not mapped
    • Does not address TAM-domain contribution
  5. 2015 High

    Solved the TAM-domain fold and identified its nucleic-acid binding surface, explaining how noncoding RNA could target NoRC.

    Evidence NMR structure determination with mutagenesis validated in vitro and in vivo

    PMID:25916849

    Open questions at the time
    • Sequence specificity of the RNA target not defined here
    • Genomic loci targeted by RNA binding not enumerated
  6. 2015 High

    Delivered chemical-probe inhibitors of the BAZ2A bromodomain, enabling pharmacological dissection of acetyl-lysine reading.

    Evidence Crystal structures of bromodomain-inhibitor complexes, ITC/competition binding, and cellular FRAP (GSK2801, BAZ2-ICR)

    PMID:25719566 PMID:25799074

    Open questions at the time
    • Genome-wide consequences of bromodomain inhibition not assessed in these studies
    • Selectivity against the paralog bromodomain context
  7. 2020 High

    Revealed a genome-organization role, showing BAZ2A interacts with SNF2H, TOP2A and cohesin to prevent active chromatin invading repressive compartments.

    Evidence Co-IP, Hi-C, ATAC-seq, ChIP-seq and genetic depletion in ground-state embryonic stem cells

    PMID:33433018

    Open questions at the time
    • Whether compartment maintenance requires the TAM or bromodomain not resolved
    • Mechanism of TOP2A-dependent H3K27me3 redistribution undefined
  8. 2020 Medium

    Placed TIP5 temporally upstream of Pten-loss oncogenesis, showing it is required for initiation but dispensable once transformation is established.

    Evidence Mouse prostate organoid model with Pten knockdown and temporally defined TIP5 depletion

    PMID:32024754

    Open questions at the time
    • Molecular targets driving the initiation requirement not pinpointed
    • Single model system
  9. 2021 High

    Connected the bromodomain to a specific enhancer mark, showing H3K14ac (EP300-deposited) recognition drives repression and oncogenic transformation.

    Evidence ChIP-seq, bromodomain point mutations, BRD inhibitor treatment and organoid transformation assays

    PMID:34403195

    Open questions at the time
    • How H3K14ac binding mediates repression mechanistically not fully resolved
    • Generality beyond prostate cells untested
  10. 2021 High

    Established the biochemical nature of TAM-domain nucleic-acid binding as sequence-nonspecific and backbone-dependent, distinguishing it from canonical methyl-CpG readers.

    Evidence EMSA, ITC, mutagenesis and X-ray crystallography

    PMID:34715126

    Open questions at the time
    • How nonspecific binding achieves locus-specific targeting in vivo
    • Relative roles of dsDNA vs dsRNA binding
  11. 2023 Medium

    Distinguished an RNA-based enhancer-repression mechanism from rDNA silencing, showing the TAM domain recruits TOP2A and KDM1A in an RNA-dependent manner.

    Evidence Co-IP, RNA-dependency experiments, pharmacological inhibition of TOP2A/KDM1A, ChIP-seq and RNA-seq in prostate cancer

    PMID:37184661

    Open questions at the time
    • Identity of the bridging RNA not defined
    • Direct vs. RNA-bridged contacts not structurally resolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the sequence-nonspecific TAM domain and combinatorial histone reading are integrated to achieve locus-specific targeting across rDNA, enhancers, and genome compartments remains unresolved.
  • No unified targeting model linking RNA, histone marks, and partner recruitment
  • Endogenous targeting RNAs unidentified

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003723 RNA binding 2 GO:0042393 histone binding 2 GO:0060090 molecular adaptor activity 2 GO:0098772 molecular function regulator activity 2 GO:0003677 DNA binding 1
Localization
GO:0005694 chromosome 2 GO:0005634 nucleus 1 GO:0005730 nucleolus 1
Pathway
R-HSA-4839726 Chromatin organization 3 R-HSA-1643685 Disease 2 R-HSA-74160 Gene expression (Transcription) 2
Partners
EP300EZH2KDM1ASNF2HTCF7L2TOP2A
Complex memberships
NoRC

Evidence

Reading pass · 13 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2014 BAZ2A (TIP5) directly interacts with EZH2 to maintain epigenetic silencing at genes repressed in metastasis in prostate cancer cells. Co-immunoprecipitation / protein interaction assay in prostate cancer cells Nature genetics Medium 25485837
2014 The PHD zinc finger domain of TIP5 recognizes unmodified H3 histone tails as an independent structural module, while the bromodomain preferentially binds H3 and H4 acetylation marks followed by a key basic residue (KacXXR motif); together these modules mediate trans-histone tail recognition required for NoRC recruitment to chromatin and transcriptional repression of rDNA. X-ray crystallography of PHD and bromodomain in free and histone-bound forms; low-resolution SAXS of PHD-bromodomain module Structure (London, England : 1993) High 25533489
2015 The TAM domain of TIP5 adopts an extended MBD-like fold with unique C-terminal extensions that form a novel RNA-binding surface; mutation of critical residues on this surface abolishes RNA binding both in vitro and in vivo, explaining how NoRC is targeted to specific genomic loci via noncoding RNA. NMR structure determination; mutagenesis with in vitro RNA-binding assays and in vivo validation Nucleic acids research High 25916849
2015 GSK2801 acts as an acetyl-lysine competitive inhibitor of the BAZ2A bromodomain (KD ~257 nM for BAZ2A), binding in a canonical acetyl-lysine competitive mode as confirmed by crystal structure; cellular activity was demonstrated by FRAP showing displacement of GFP-BAZ2A from acetylated chromatin. Crystal structure of bromodomain–inhibitor complex; isothermal titration calorimetry / competition binding; FRAP in cells Journal of medicinal chemistry High 25799074
2015 BAZ2-ICR occupies the BAZ2A bromodomain acetyl-lysine pocket through an intramolecular aromatic stacking interaction that efficiently fills the shallow binding site, as revealed by structure-based design. Structure-based drug design; X-ray crystallography of inhibitor–bromodomain complex Journal of medicinal chemistry High 25719566
2013 The TAM domain of Tip5 functions as the nucleolar localization and nuclear matrix targeting module, while AT-hooks are required for nucleolar targeting but do not mediate nuclear matrix association; Tip5 overexpression facilitates rDNA association with the nuclear matrix and increases DNase I inaccessibility, regulating large-scale rDNA chromatin organization. Domain deletion/mutation analysis; nuclear fractionation; DNase I accessibility assay; overexpression and localization imaging Nucleic acids research Medium 23580549
2013 NuRD complex directly binds to the TIP5 promoter and negatively regulates TIP5 expression, thereby limiting TIP5-mediated recruitment of DNA methyltransferase to rDNA promoters and maintaining their unmethylated state. ChIP at TIP5 promoter; knockdown of NuRD components with measurement of TIP5 expression and rDNA methylation Biochemical and biophysical research communications Medium 23796711
2018 TIP5 physically interacts with TCF7L2 (identified by co-immunoprecipitation and GST pull-down) and enhances the interaction between β-catenin and TCF7L2, thereby activating Wnt/β-catenin signaling in hepatocellular carcinoma cells. Co-immunoprecipitation; GST pull-down assay; reporter and functional cell assays Molecular medicine reports Medium 29620186
2020 In ground-state embryonic stem cells, BAZ2A interacts with SNF2H, DNA topoisomerase 2A (TOP2A), and cohesin on chromatin; BAZ2A depletion increases chromatin accessibility at B compartments and dysregulates H3K27me3 genome occupancy in a TOP2A-dependent manner, demonstrating that BAZ2A limits invasion of active chromatin domains into repressive compartments. Co-immunoprecipitation; Hi-C genome architecture analysis; ATAC-seq; ChIP-seq; genetic depletion (BAZ2A KO/KD) The EMBO journal High 33433018
2021 BAZ2A bromodomain specifically binds H3K14ac-marked chromatin at inactive enhancers; BAZ2A-BRD mutations or pharmacological inhibition of the BAZ2A-BRD/H3K14ac interaction impairs prostate cancer stem cell features and Pten-loss-driven oncogenic transformation in organoids. BAZ2A-mediated repression at these enhancers is linked to EP300, which acetylates H3K14. ChIP-seq for BAZ2A and H3K14ac; bromodomain point mutations; BRD inhibitor treatment; organoid transformation assay EMBO reports High 34403195
2021 The BAZ2A TAM domain binds double-stranded DNA and double-stranded RNA in a sequence-nonspecific, backbone-dependent manner (distinct from canonical MBD methyl-CpG recognition), as established by EMSA, ITC, mutagenesis, and X-ray crystallography. EMSA; isothermal titration calorimetry; mutagenesis; X-ray crystallography The Journal of biological chemistry High 34715126
2023 In prostate cancer, the BAZ2A TAM domain mediates interaction with TOP2A and KDM1A through an RNA-dependent mechanism; pharmacological inhibition of TOP2A or KDM1A upregulates BAZ2A-repressed genes controlled by inactive enhancers, whereas rRNA gene silencing is unaffected, revealing a distinct RNA-based gene repression mechanism separate from rDNA silencing. Co-immunoprecipitation; RNA-dependency experiments; pharmacological inhibition of TOP2A and KDM1A; ChIP-seq; RNA-seq Life science alliance Medium 37184661
2020 TIP5 is required for the initiation of prostate cancer transformation of luminal cells driven by Pten-loss in organoids, but is dispensable once transformation is established, placing TIP5 upstream of Pten-loss-mediated oncogenesis in a defined cellular context. Mouse prostate organoid model; Pten knockdown; TIP5 depletion with defined temporal order; cross-species gene expression analysis Proceedings of the National Academy of Sciences of the United States of America Medium 32024754

Source papers

Stage 0 corpus · 23 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2014 BAZ2A (TIP5) is involved in epigenetic alterations in prostate cancer and its overexpression predicts disease recurrence. Nature genetics 126 25485837
2015 Discovery and Characterization of GSK2801, a Selective Chemical Probe for the Bromodomains BAZ2A and BAZ2B. Journal of medicinal chemistry 107 25799074
2015 Structure enabled design of BAZ2-ICR, a chemical probe targeting the bromodomains of BAZ2A and BAZ2B. Journal of medicinal chemistry 75 25719566
2014 Molecular basis of histone tail recognition by human TIP5 PHD finger and bromodomain of the chromatin remodeling complex NoRC. Structure (London, England : 1993) 59 25533489
2021 BAZ2A-mediated repression via H3K14ac-marked enhancers promotes prostate cancer stem cells. EMBO reports 30 34403195
2013 Large-scale organization of ribosomal DNA chromatin is regulated by Tip5. Nucleic acids research 26 23580549
2015 A novel RNA binding surface of the TAM domain of TIP5/BAZ2A mediates epigenetic regulation of rRNA genes. Nucleic acids research 25 25916849
2017 Discovery of BAZ2A bromodomain ligands. European journal of medicinal chemistry 23 28837921
2005 Toutatis, a TIP5-related protein, positively regulates Pannier function during Drosophila neural development. Development (Cambridge, England) 20 16141224
2020 BAZ2A safeguards genome architecture of ground-state pluripotent stem cells. The EMBO journal 19 33433018
2006 Fusion of ETV6 with an intronic sequence of the BAZ2A gene in a paediatric pre-B acute lymphoblastic leukaemia with a cryptic chromosome 12 rearrangement. British journal of haematology 19 16643428
2020 TIP5 primes prostate luminal cells for the oncogenic transformation mediated by PTEN-loss. Proceedings of the National Academy of Sciences of the United States of America 16 32024754
2018 Structural Analysis of Small-Molecule Binding to the BAZ2A and BAZ2B Bromodomains. ChemMedChem 14 29770599
2013 CHD4/NuRD maintains demethylation state of rDNA promoters through inhibiting the expression of the rDNA methyltransferase recruiter TIP5. Biochemical and biophysical research communications 12 23796711
2022 LINC00885 promotes cervical cancer progression through sponging miR-3150b-3p and upregulating BAZ2A. Biology direct 11 35012615
2018 The transcription factor 7 like 2‑binding protein TIP5 activates β‑catenin/transcription factor signaling in hepatocellular carcinoma. Molecular medicine reports 11 29620186
2021 Structural basis of the TAM domain of BAZ2A in binding to DNA or RNA independent of methylation status. The Journal of biological chemistry 9 34715126
2022 Identification of a BAZ2A-Bromodomain Hit Compound by Fragment Growing. ACS medicinal chemistry letters 8 36105334
2023 Nasopharyngeal carcinoma derived exosomes regulate the proliferation and migration of nasopharyngeal carcinoma cells by mediating the miR-99a-5p BAZ2A axis. Brazilian journal of otorhinolaryngology 5 37925811
2023 BAZ2A-RNA mediated association with TOP2A and KDM1A represses genes implicated in prostate cancer. Life science alliance 4 37184661
2023 Reevaluation of bromodomain ligands targeting BAZ2A. Protein science : a publication of the Protein Society 4 37574751
2016 Differential enrichment of TTF-I and Tip5 in the T-like promoter structures of the rDNA contribute to the epigenetic response of Cyprinus carpio during environmental adaptation. Biochemistry and cell biology = Biochimie et biologie cellulaire 2 27458840
2026 Unusual backfolded binding poses of BAZ2A bromodomain binders. Acta crystallographica. Section D, Structural biology 0 42233460

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