Affinage

CBX2

Chromobox protein homolog 2 · UniProt Q14781

Length
532 aa
Mass
56.1 kDa
Annotated
2026-06-09
100 papers in source corpus 35 papers cited in narrative 35 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/9 claims corpus-supported (89%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CBX2 is the chromodomain-containing subunit of canonical PRC1 that serves as the obligate nucleating scaffold for Polycomb-mediated chromatin compaction and transcriptional repression (PMID:30514760, PMID:9312051). Through an internal charged intrinsically disordered region it drives liquid-liquid phase separation of PRC1 into nuclear condensates that concentrate DNA and nucleosomes, and condensate formation by other PRC1 subunits (Ring1b, Mel18, Phc1) depends on CBX2; the same charged-region point mutations that abolish phase separation also eliminate nucleosome compaction and cause axial patterning defects in mice, linking phase separation, chromatin compaction, and development to one domain (PMID:31171700, PMID:30514760). CBX2 reads chromatin combinatorially, using its chromodomain to bind H3K27me3 and its AT-hook to bind AT-rich satellite DNA, and it uniquely associates stably with mitotic chromosomes to recruit the rest of PRC1 there (PMID:25801166, PMID:25232004). Its histone-mark specificity is tuned by phosphorylation: chromodomain Ser-42 phosphorylation switches reading preference from H3K9me3 toward H3K27me3, and CK2 phosphorylation of the serine-rich region enhances H3K27me3-nucleosome binding while reducing AT-hook DNA binding and is required to repress p21 (PMID:20493168, PMID:28992316). Beyond reading repressive marks, CBX2 nucleates heterochromatin formation by sequentially recruiting the H3K9 methyltransferases G9a and SUV39H1, and its loss destabilizes large-scale chromatin structure, decondenses satellite DNA, and causes chromosome instability (PMID:34274396, PMID:32870972). Developmentally, CBX2 represses Hox genes to control axial patterning and acts upstream of Sry to stabilize testis fate by directly repressing Wnt/ovary-promoting genes such as Lef1, with loss-of-function causing XY sex reversal in mice and humans (PMID:9641679, PMID:9043087, PMID:31116734, PMID:19361780). CBX2 protein stability is governed by a SUMO-ubiquitin degradation pathway (CBX4 SUMO ligase, RNF4 ubiquitin ligase) opposed by deubiquitinases USP33 and USP27X (PMID:29467492, PMID:39256572, PMID:38030604). Noncanonically and independently of PRC1, CBX2 assembles a RACK1-HDAC1 corepressor complex that reduces H3K27ac at interferon-stimulated gene promoters to suppress interferon signaling and enable immune evasion (PMID:39883845). Loss-of-function mutation of CBX2 in a 46,XY individual establishes its requirement for human testis determination (PMID:19361780).

Mechanistic history

Synthesis pass · year-by-year structured walk · 26 steps
  1. 1997 High

    Establishing that mammalian CBX2 is a bona fide Polycomb-group transcriptional repressor and a complex component answered whether the protein functions in chromatin silencing.

    Evidence transcriptional repressor assays and reciprocal interaction mapping showing Ring1A/Ring1B bind the C-terminal repressor domain in transfected cells

    PMID:9312051

    Open questions at the time
    • Did not define genomic targets or mechanism of repression
    • No structural basis for the Ring1 interaction
  2. 1997 High

    Knockout phenotyping established the in vivo developmental role of CBX2 in Hox repression and proliferation, linking molecular silencing to organismal patterning.

    Evidence targeted disruption in mice producing homeotic skeletal transformations, malformations, and impaired lymphocyte/fibroblast expansion

    PMID:9043087

    Open questions at the time
    • Did not identify direct target loci
    • Proliferation defect mechanism unresolved at this stage
  3. 1998 High

    Defining the native complex composition addressed which Polycomb partners CBX2 associates with and showed cell-type-specific complex heterogeneity.

    Evidence reciprocal Co-IP and gel filtration from embryonic extracts with domain mapping showing M33-BMI1 but not M33-RAE28 interaction

    PMID:9571155

    Open questions at the time
    • Stoichiometry and full subunit roster not determined
    • Functional consequence of distinct complexes untested
  4. 1998 High

    Placing CBX2 upstream of Sry answered where in the sex-determination cascade it acts, establishing a genetic role in testis fate.

    Evidence targeted KO in mice causing XY male-to-female sex reversal with retarded genital ridge formation

    PMID:9641679

    Open questions at the time
    • Direct target genes of repression not identified here
    • Molecular mechanism upstream of Sry undefined at this stage
  5. 2000 Medium

    Showing CBX2 antagonizes retinoic acid signaling addressed how it controls the temporal sequence of Hox activation.

    Evidence expression analysis and RA treatment of M33-/- embryos showing premature Hoxd4/Hoxd11 activation

    PMID:10926763

    Open questions at the time
    • Single lab
    • Direct molecular link between CBX2 and RA-responsive elements not shown
  6. 2004 High

    Genetic epistasis placed CBX2 upstream of the INK4a/E2F axis, explaining its proliferative control role at the pathway level.

    Evidence BrdU/p16INK4a readouts in M33-/- fibroblasts with dominant-negative E2F rescue

    PMID:15377996

    Open questions at the time
    • Direct binding of CBX2 to the INK4a locus not demonstrated here
    • Lymphocyte defect mechanism not resolved
  7. 2005 High

    ChIP demonstration of direct locus occupancy at Ad4BP/SF1 connected CBX2 to specific target genes during organ development.

    Evidence KO phenotyping with western/IHC/RT-PCR plus ChIP in adrenocortical cells showing PcG complex binding the Ad4BP/SF1 locus

    PMID:15899914

    Open questions at the time
    • Histone-mark context at the locus not profiled
    • Generalizability beyond adrenal/spleen unclear
  8. 2006 Medium

    Identifying a functional NLS clarified how CBX2 achieves nuclear localization required for its chromatin function.

    Evidence deletion mutagenesis and GFP-fusion targeting assay

    PMID:17043400

    Open questions at the time
    • Single method, single lab
    • Regulation of NLS use not addressed
  9. 2010 High

    Identifying chromodomain Ser-42 phosphorylation as a switch for histone-mark reading answered how CBX2 binding specificity is regulated.

    Evidence mass spectrometry site identification with in vitro phosphorylation and peptide-binding assays showing reduced H3K9me3 and increased H3K27me3 binding

    PMID:20493168

    Open questions at the time
    • Responsible kinase not identified
    • In vivo functional consequence of Ser-42 phosphorylation untested
  10. 2014 High

    Demonstrating CBX2-specific stable mitotic-chromosome association answered how PRC1 is recruited to chromosomes during mitosis.

    Evidence quantitative live imaging, FRAP, PRC1/PRC2 depletion and domain deletion in ES and tumor cells showing CBX2 N-terminus mediates recruitment and C-terminus immobilization

    PMID:25232004

    Open questions at the time
    • The chromatin determinant retaining CBX2 in mitosis not defined
    • Functional importance of mitotic retention for epigenetic memory untested
  11. 2015 High

    Dissecting chromodomain versus AT-hook targeting answered how CBX2 achieves parent-of-origin-specific PRC1 deposition.

    Evidence domain mutagenesis, ChIP, and co-localization in mouse zygotes showing CD binds H3K27me3 and AT-hook binds satellite DNA, with HP1β excluding PRC1 from maternal PCH

    PMID:25801166

    Open questions at the time
    • How the chromodomain restrains AT-hook DNA binding mechanistically unresolved
    • Generality beyond the zygote untested
  12. 2017 High

    Identifying CK2 phosphorylation of the serine-rich region defined a regulatory input that tunes nucleosome versus DNA binding and repression.

    Evidence in vitro CK2 kinase assay, nucleosome pull-down, EMSA, and SR-deletion repression assay at p21

    PMID:28992316

    Open questions at the time
    • In vivo regulation of CK2-CBX2 phosphorylation not shown
    • Interplay with Ser-42 chromodomain phosphorylation not addressed
  13. 2018 High

    Reconstitution established CBX2 as the nucleating driver of PRC1 condensate formation via its IDR, reframing PRC1 assembly as a phase-separation process.

    Evidence site-directed mutagenesis, live imaging, in vitro LLPS, and H3K27me3-null cells showing other subunits' condensation depends on CBX2

    PMID:30514760

    Open questions at the time
    • Relationship between condensates and gene-specific silencing not fully resolved
    • Role of H3K27me3 in condensate function downplayed but not excluded
  14. 2019 High

    Linking phase separation to compaction and patterning through shared mutations answered whether condensation is functionally essential rather than incidental.

    Evidence reconstituted PRC1 LLPS assay with charged-region point mutants that also abolish compaction and cause mouse axial defects

    PMID:31171700

    Open questions at the time
    • Direct demonstration that condensates cause repression at endogenous loci not shown
    • Quantitative threshold for functional condensation undefined
  15. 2019 High

    Genome-wide profiling plus double-mutant rescue established the molecular mechanism by which CBX2 stabilizes testis fate.

    Evidence H3K27me3/H3K4me3 ChIP-seq, Cbx2-/-;Wnt4-/- rescue, and CBX2 ChIP at Lef1 in Sertoli cells

    PMID:31116734

    Open questions at the time
    • Full set of CBX2-bound sex-determining loci not enumerated
    • Temporal dynamics of bivalency resolution not tracked
  16. 2009 Medium

    A human loss-of-function mutation confirmed the conserved requirement of CBX2 for testis determination in humans.

    Evidence CBX2 sequencing in a 46,XY girl with ovaries, pathway placement upstream of SRY

    PMID:19361780

    Open questions at the time
    • Single case
    • Functional consequence of the variant assigned by analogy with mouse
  17. 2009 Medium

    Genetic interaction with Asxl1 placed CBX2 in a shared Hox-silencing pathway during axial patterning.

    Evidence compound Asxl1;M33 mutant mouse genetics with enhanced skeletal transformations

    PMID:19833123

    Open questions at the time
    • Biochemical basis of the interaction unknown
    • Single lab epistasis
  18. 2018 Medium

    Identifying CBX4 and RNF4 defined a SUMO-triggered ubiquitin degradation pathway controlling CBX2 protein levels.

    Evidence Co-IP, SUMOylation/ubiquitination assays, and CBX4/RNF4 knockdown in leukemia cells with SAHA-induced destabilization

    PMID:29467492

    Open questions at the time
    • Single lab
    • Physiological trigger of degradation beyond HDAC inhibition unclear
  19. 2020 High

    Showing that CBX2 loss decondenses satellite DNA and causes genome instability established its role in heterochromatin homeostasis beyond gene-specific silencing.

    Evidence ATAC-seq, transcriptomics, and cytogenetics/FISH in Cbx2-/- fibroblasts revealing sister chromatid recombination and centromere/telomere defects

    PMID:32870972

    Open questions at the time
    • Mechanistic link between PRC1 condensates and centromere/telomere integrity not defined
    • Direct versus indirect effects on satellite chromatin unresolved
  20. 2021 Medium

    Demonstrating sequential G9a/SUV39H1 recruitment defined how CBX2 nucleates H3K9-methylated heterochromatin from H3K27me3 domains.

    Evidence fluorescence microscopy, ChIP, and domain/inhibitor experiments showing HP1α-independent generation of dual H3K27me3/H3K9me3 domains

    PMID:34274396

    Open questions at the time
    • Single lab
    • Direct biochemical interaction with G9a/SUV39H1 not mapped
  21. 2021 Medium

    Single-molecule quantification of condensate stoichiometry and boundary control connected CBX2 LLPS to H3K27me3 deposition and differentiation.

    Evidence single-molecule imaging, ATAC-seq, ChIP-seq and differentiation assays in mouse ESCs (preprint)

    PMID:38370615

    Open questions at the time
    • Preprint status
    • Causality between sparse CBX2 and boundary demarcation correlative
  22. 2023 High

    Identifying USP33 (and acetylation by GCN5) defined a deubiquitination axis opposing CBX2 degradation and mapping its regulated lysines.

    Evidence proteomics/ubiquitinomics, Co-IP, site-specific chain mapping at K277, and K199 acetylation analysis

    PMID:39256572

    Open questions at the time
    • Single lab
    • Physiological signals controlling USP33 recruitment unclear
  23. 2023 Medium

    Defining a GSK3β-USP27X axis added a second deubiquitinase route stabilizing CBX2.

    Evidence mass spectrometry, Co-IP, and in vitro kinase assay showing GSK3β phosphorylation of USP27X enhances CBX2 deubiquitination

    PMID:38030604

    Open questions at the time
    • Limited independent validation
    • Relative contributions of USP33 versus USP27X unresolved
  24. 2023 High

    Identifying the CBX2-RACK1-HDAC1 corepressor complex established a PRC1-independent role in suppressing interferon-stimulated genes and immune evasion.

    Evidence mass spectrometry, Co-IP, H3K27ac ChIP, RNA-seq and syngeneic tumor models

    PMID:39883845

    Open questions at the time
    • Structural organization of the RACK1-HDAC1 complex undefined
    • Relationship to canonical PRC1 condensates not addressed
  25. 2023 High

    Mosaic in vivo analysis showed CBX2 condensates are required to repress spermatogonial stem-cell genes and maintain germ cells, extending phase separation to germline development.

    Evidence mosaic/conditional Cbx2 KO, single-cell RNA-seq, imaging and IDR-mutant knock-in in mouse testis

    PMID:37553262

    Open questions at the time
    • Direct target loci of condensates in spermatogonia not enumerated
    • Mechanism of stage-specific recruitment unresolved
  26. 2021 Medium

    Development of a selective chromodomain inhibitor (SW2_152F) provided a chemical tool to interrogate CBX2 chromatin binding and its role in cancer differentiation.

    Evidence DNA-encoded library selection, Kd and selectivity measurements, cellular chromatin-binding and neuroendocrine differentiation assays

    PMID:33950564

    Open questions at the time
    • Single lab
    • Off-target effects in vivo not characterized

Open questions

Synthesis pass · forward-looking unresolved questions
  • How CBX2's phosphorylation-tuned reading, condensate nucleation, ubiquitin/SUMO turnover, and PRC1-independent corepressor activity are integrated to select specific target loci in each developmental and disease context remains unresolved.
  • No unified model connecting condensate state to locus-specific repression
  • Structural basis of CBX2 scaffolding within PRC1 condensates undefined
  • Switch between canonical PRC1 and noncanonical RACK1-HDAC1 functions uncharacterized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0042393 histone binding 5 GO:0003677 DNA binding 3 GO:0060090 molecular adaptor activity 3 GO:0140110 transcription regulator activity 3 GO:0140313 molecular sequestering activity 2
Localization
GO:0005634 nucleus 3 GO:0005654 nucleoplasm 3 GO:0000228 nuclear chromosome 2 GO:0005829 cytosol 1
Pathway
R-HSA-1266738 Developmental Biology 4 R-HSA-4839726 Chromatin organization 4 R-HSA-392499 Metabolism of proteins 3 R-HSA-74160 Gene expression (Transcription) 3 R-HSA-168256 Immune System 2
Partners
BMI1EZH2HDAC1RACK1RING1ARING1BRNF4USP33
Complex memberships
CBX2-RACK1-HDAC1 corepressor complexcanonical PRC1

Evidence

Reading pass · 35 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2019 CBX2 drives liquid-liquid phase separation (LLPS) of canonical PRC1 into droplets in vitro at low concentrations and physiological salt. Point mutations in an internal charged disordered region of CBX2 eliminate phase separation in vitro and puncta formation in cells; these same mutations were previously shown to eliminate nucleosome compaction in vitro and cause axial patterning defects in mice, linking phase separation, chromatin compaction, and developmental function to the same domain. Reconstituted PRC1 in vitro phase-separation assay; point mutagenesis; fluorescence live-cell imaging Genes & development High 31171700
2018 CBX2 undergoes liquid-liquid phase separation to form nuclear condensates with liquid-like properties. The intrinsically disordered region (IDR) of CBX2 promotes condensate formation in vitro and in vivo. CBX2 condensates concentrate DNA and nucleosomes. H3K27me3 (PRC2-deposited mark) has minimal effect on CBX2 condensate formation. Condensate formation of other CBX2-PRC1 subunits (Ring1b, Mel18, Phc1) depends on CBX2, establishing CBX2 as the nucleating component for PRC1 condensate assembly. Site-directed mutagenesis; fluorescence live-cell imaging; in vitro LLPS assay; genetic engineering (H3K27me3-null cells); co-localization assays The Journal of biological chemistry High 30514760
1997 Mouse M33 (CBX2) acts as a transcriptional repressor in transiently transfected cells. The C-terminal region of M33 constitutes a repressor domain. Ring1A and Ring1B directly interact with this repressor domain of M33 and co-localize with M33 in nuclear domains, forming components of mammalian Polycomb-group protein complexes. Transcriptional repressor assay in transfected cells; yeast two-hybrid and direct protein interaction assays; immunofluorescence co-localization The EMBO journal High 9312051
1998 RAE28 (Rae28/Phc2), BMI1, and M33 (CBX2) co-immunoprecipitate from mouse embryonic nuclear extracts and co-purify as members of large multimeric complexes (gel filtration). M33 interacts homotypically and with BMI1 but not with RAE28; RAE28 interacts with BMI1 but not M33. Different Polycomb-group complexes of distinct composition form in different cell types. Co-immunoprecipitation from embryonic extracts; gel filtration; domain mapping of interaction regions Biochemical and biophysical research communications High 9571155
1998 Loss-of-function of M33 (CBX2) in mice causes male-to-female sex reversal in XY animals. M33 deficiency retards formation of genital ridges and affects gonadal growth near the time of Sry expression, placing M33 upstream of Sry in the sex-determination cascade. Targeted gene disruption (homologous recombination) in mice; histological and phenotypic analysis of M33cterm/M33cterm mutants Nature High 9641679
1997 Homozygous M33 (CBX2) knockout mice show homeotic transformations of the axial skeleton, sternal and limb malformations, growth retardation, and failure to expand lymphocytes and fibroblasts in vitro, demonstrating a role for M33 in Hox gene repression and cell proliferation control. Targeted homologous recombination in ES cells; skeletal analysis; in vitro cell proliferation assays; retinoic acid treatment experiments Development (Cambridge, England) High 9043087
2015 Cbx2 directs PRC1 to paternal pericentric heterochromatin (pat-PCH) in mouse zygotes via its chromodomain (CD) binding H3K27me3 and its AT-hook (AT) binding AT-rich major satellite repeats. The CD of Cbx2 prevents its AT-hook from interacting with DNA at PCH marked by H3K9me3 and HP1β. HP1β (not H3K9me3) is responsible for excluding PRC1 from maternal PCH, demonstrating parent-of-origin-specific PRC1 targeting. Loss-of-function studies; chromodomain and AT-hook domain mutagenesis; ChIP; co-localization imaging in mouse zygotes Molecular cell High 25801166
2014 Cbx2 stably associates with mitotic chromosomes independently of PRC1 or PRC2, while other Cbx-family proteins bind dynamically. Cbx2 is required to recruit the PRC1 complex to mitotic chromosomes. The N-terminus of Cbx2 is needed for recruitment to mitotic chromosomes, whereas the C-terminus is required for its immobilization there. Quantitative live-cell imaging; FRAP; depletion of PRC1/PRC2 components; domain deletion analysis; fluorescence microscopy in mouse ES and tumor cells Molecular biology of the cell High 25232004
2010 Mouse Cbx2 is highly phosphorylated in certain cell lines. Mass spectrometry identified serine-42 in the chromodomain as a phosphorylation site. Phosphorylation of the chromodomain on Ser-42 in vitro reduces binding to H3K9me3 and increases binding to H3K27me3 peptides, demonstrating that chromodomain phosphorylation acts as a molecular switch changing histone-mark reading specificity. Alkaline phosphatase treatment; mass spectrometry; in vitro phosphorylation; peptide-binding assay Biochemical and biophysical research communications High 20493168
2017 CBX2 is stably phosphorylated in vivo, primarily at serine residues in a serine-rich (SR) region that constitute CK2 consensus sites. CK2 efficiently phosphorylates the SR region in vitro. CK2-phosphorylated CBX2 shows high specificity for H3K27me3-modified nucleosomes (pull-down assay) and reduced AT-hook-associated DNA-binding activity (EMSA). Mutant CBX2 lacking the SR region or neighboring acidic-residue cluster fails to repress p21 transcription. In vitro CK2 phosphorylation; nucleosome pull-down assay; EMSA; domain deletion mutagenesis; transcriptional repression assay Journal of biochemistry High 28992316
2002 M33 (CBX2) in adult mouse liver is predominantly cytoplasmic (high-mobility 60-kDa phosphoforms), but nuclear isoforms (66 and 70 kDa) appear after partial hepatectomy near the peak of DNA synthesis. Alkaline phosphatase treatment of nuclear isoforms converts them to the cytoplasmic mobility form, indicating that phosphorylation-associated nuclear translocation occurs in a cell-cycle-dependent manner. Subcellular fractionation; immunoblotting; alkaline phosphatase treatment; immunocytochemistry of freeze-substituted tissue; BrdU incorporation Biochemical and biophysical research communications Medium 11855817
2006 A functional nuclear localization signal (NLS) was identified in M33 (CBX2). Deletion of this specific NLS motif abolishes nuclear localization; a GFP fusion to this motif is sufficient for nuclear targeting. Deletion mutagenesis; GFP-fusion nuclear localization assay Zoological science Medium 17043400
2004 M33 (CBX2)-deficient mouse embryonic fibroblasts show impaired S-phase entry and accumulation of p16INK4a, with a senescent phenotype. This proliferative defect is bypassed by a dominant-negative form of E2F, placing M33 upstream of the INK4a/E2F pathway in cell-cycle control. M33 also controls expansion of B- and T-lymphocyte precursors. BrdU incorporation assay; western blot for p16INK4a; transfection of dominant-negative E2F (epistasis); M33-/- mouse-derived fibroblasts and lymphocytes Oncogene High 15377996
2000 In M33-null mice, the window of retinoic acid (RA) responsiveness for Hoxd4 is opened earlier and Hoxd11 expression is activated earlier in development, showing that M33 antagonizes the RA pathway and controls the temporal activation sequence of Hox genes. Gene expression analysis in M33-/- embryos; RA treatment experiments; in situ hybridization Developmental biology Medium 10926763
2005 M33 (CBX2) is required for normal splenic vascular and adrenal gland formation. M33 knockout mice show markedly reduced Ad4BP/SF1 (Nr5a1) expression as confirmed by western blot, immunohistochemistry, and RT-PCR. ChIP of adrenocortical Y-1 cells reveals direct binding of M33-containing PcG complexes to the Ad4BP/SF1 gene locus, placing M33 as a direct upstream regulator of Ad4BP/SF1. M33 knockout mouse phenotypic analysis; western blot; immunohistochemistry; RT-PCR; chromatin immunoprecipitation (ChIP) Blood High 15899914
2009 Loss-of-function mutations in human CBX2 in a 46,XY girl with female phenotype (including ovaries) establishes CBX2 as acting upstream of SRY in the human sex-determination cascade. Sequencing of CBX2 in human patient; functional analysis placing CBX2 upstream of SRY based on mouse ortholog phenotype and human mutation American journal of human genetics Medium 19361780
2019 CBX2 is required to stabilize testis fate by directly repressing Wnt/ovary-promoting genes. Genome-wide H3K27me3 and H3K4me3 profiling shows that testis and ovary sex-determining genes are bivalent before sex determination. Deletion of Wnt4 rescues Sry expression and testis development in XY Cbx2-/- mice (genetic epistasis). CBX2 directly binds the Wnt target gene Lef1 locus in Sertoli cells. Genome-wide ChIP-seq (H3K27me3/H3K4me3); Cbx2-/-;Wnt4-/- double-mutant rescue; ChIP for CBX2 occupancy at Lef1 PLoS genetics High 31116734
2018 CBX2 promotes antiviral innate immunity in macrophages by binding to and recruiting the H3K27me3 demethylase Jmjd3 to the Ifnb promoter, leading to demethylation of H3K27me3 and increased IFN-β transcription. Cbx2 knockdown impairs virus-induced IFN-β production, and heterozygous Cbx2 knockout mice are more susceptible to VSV challenge. Knockdown/knockout in macrophages; VSV challenge in vivo; Co-IP/binding assay of Cbx2-Jmjd3; ChIP at Ifnb promoter; H3K27me3 demethylation assay Protein & cell Medium 30357595
2018 HDAC inhibitor SAHA destabilizes CBX2 protein via a SUMO-triggered ubiquitin-mediated pathway in leukemia cells. CBX4 was identified as the E3 SUMO ligase and RNF4 as the E3 ubiquitin ligase responsible for CBX2 degradation. Co-IP; ubiquitination and SUMOylation assays; knockdown of CBX4 and RNF4; protein stability assays Oncogene Medium 29467492
2023 USP33 deubiquitinates CBX2 by removing K27- and K48-linked ubiquitin chains at lysine K277, thereby stabilizing CBX2. Acetylation of CBX2 at K199, catalyzed by GCN5 acetyltransferase, enhances the interaction between CBX2 and USP33, promoting further deubiquitination and stabilization. Proteomics and ubiquitinomics screening; Co-IP; ubiquitination assay; mass spectrometry mapping of modification sites; overexpression/depletion experiments Oncogene High 39256572
2023 GSK3β directly binds to and phosphorylates USP27X, which enhances the interaction between USP27X and CBX2, leading to CBX2 stabilization through deubiquitination. This defines a GSK3β-USP27X-CBX2 axis controlling CBX2 protein stability. Mass spectrometry; Co-IP; in vitro kinase assay; overexpression/depletion experiments Cell death & disease Medium 38030604
2021 CBX2 chromodomain inhibitor SW2_152F (Kd ~80 nM, 24-1000-fold selective over other CBX paralogs in vitro) is cell-permeable, selectively inhibits CBX2 chromatin binding in cells, and blocks neuroendocrine differentiation of prostate cancer cells in response to androgen deprivation. DNA-encoded library (DEL) selection; binding affinity measurement; cellular chromatin occupancy assay; neuroendocrine differentiation assay Chembiochem Medium 33950564
2021 Approximately 3 CBX2 proteins nucleate many PRC1 and PRC2 subunits to form one non-stoichiometric condensate in mouse ESCs. Sparse CBX2 prevents Polycomb proteins from migrating to constitutive heterochromatin, demarcates spatial boundaries of facultative heterochromatin, controls H3K27me3 deposition, and is required for cellular differentiation. LLPS of CBX2 is required for H3K27me3 deposition and differentiation. Genetic engineering; live-cell single-molecule imaging; ATAC-seq; ChIP-seq; differentiation assays bioRxivpreprint Medium 38370615
2021 M33/CBX2 compacts chromatin into DAPI-intense heterochromatin domains in cells by forming nuclear bodies that require H3K27me3 binding. These M33 nuclear bodies sequentially recruit G9a and then SUV39H1 to create H3K9-methylated chromatin, independently of HP1α, generating domains containing both H3K27me3 and H3K9me3. Fluorescence microscopy; ChIP; overexpression/domain mutagenesis; inhibitor experiments in cells Biochimica et biophysica acta. Molecular cell research Medium 34274396
2023 CBX2 suppresses interferon signaling independent of its canonical PRC1 function. CBX2 directly interacts with RACK1 and facilitates recruitment of HDAC1, which reduces H3K27ac at promoters of interferon-stimulated genes, thereby suppressing IFN signaling and enabling immune evasion. This noncanonical CBX2-RACK1-HDAC1 corepressor complex is distinct from PRC1. Mass spectrometry screening of CBX2-interacting proteins; Co-IP; ChIP for H3K27ac; syngeneic tumor models; RNA-seq transcriptional analysis Proceedings of the National Academy of Sciences of the United States of America High 39883845
2023 CBX2 directly represses PTEN transcription by recruiting EZH2 and modulating H3K27me3 levels at the PTEN promoter, thereby activating the AKT/mTOR signaling pathway in glioma cells. ChIP; western blot; siRNA knockdown; EZH2 co-immunoprecipitation; in vivo xenograft Frontiers in pharmacology Medium 39114365
2021 CBX2 and EZH2 cooperatively downregulate PPAR pathway genes and tumor suppressor genes by co-binding their promoters, as shown by ChIP-seq analysis of their occupancy. ChIP-seq; RNA-seq; knockdown experiments in LUAD cells Molecular therapy. Nucleic acids Medium 35070495
2023 CBX2 cooperates with EZH2 to mediate H3K27me3 enrichment at the promoter of SIAH2, suppressing its transcription in HCC. Loss of SIAH2 leads to WNK1 accumulation (by blocking SIAH2-mediated ubiquitination/degradation of WNK1), driving glycolysis. CBX2 and EZH2 interaction at the SIAH2 locus was demonstrated by ChIP. ChIP for H3K27me3 at SIAH2 promoter; Co-IP of CBX2 and EZH2; GSEA; ubiquitination assay for WNK1 Experimental cell research Medium 36780970
2022 CBX2 promotes mTORC1 signaling and inhibits DREAM complex activity to drive breast cancer growth. CBX2 represses mTORC1 inhibitors and the tumor suppressor RBL2. Loss of RBL2 repression by CBX2 inhibits DREAM complex activity, relieving suppression of E2F signaling. A chromatin-binding-deficient CBX2 mutant fails to rescue the growth phenotype, indicating that chromatin binding is required. CBX2 knockdown; ectopic expression of CBX2 wild-type vs. chromatin-binding-deficient mutant; RNA-seq; GSEA; SW2_152F chromodomain inhibitor; western blot Cancers Medium 35884550
2023 CBX2 in differentiating spermatogonia is required to repress genes active in spermatogonial stem cells. CBX2 forms condensates that co-localize with target genes in differentiating spermatogonia. Single-cell analyses of mosaic Cbx2 mutant testes show CBX2 is specifically required to produce differentiating A1 spermatogonia. The IDR region responsible for compaction and phase separation is needed for long-term germ cell maintenance in vivo. Cbx2 conditional/mosaic knockout in mouse; single-cell RNA-seq; immunofluorescence; domain deletion (IDR mutant) knock-in Genes & development High 37553262
2025 In vitro screening based on the crystal structure of CBX2 identified CG3-46 as a nonpeptide small-molecule inhibitor of the CBX2 chromodomain. CG3-46 inhibits CBX2-H3K27me3 histone interaction in cells and reduces growth of MDA-MB-231 cells with increased expression of a CBX2 target gene. In silico screening using CBX2 crystal structure; binding validation; cellular chromatin-interaction assay; cell growth assay Biochemical and biophysical research communications Medium 40315569
2026 CBX2 condensates facilitate recruitment of DNA double-strand break (DSB) repair factors PARP1, 53BP1, and BRCA1 to chromatin in high-grade serous ovarian carcinoma, promoting homologous recombination repair and drug resistance. Ibrutinib was identified as an inhibitor of HGSOC cells with CBX2 condensates. Drug screening; chromatin fractionation; immunofluorescence for DSB repair factors; patient-derived organoid models; CRISPR CBX2 KO Cell death & disease Medium 41888115
2009 Asxl1 genetically interacts with Cbx2/M33 in mice: compound Asxl1;M33 mutant embryos show enhanced axial skeletal transformations compared to single mutants, placing Asxl1 and M33 in the same pathway controlling Hox gene silencing during axial patterning. Double-mutant mouse genetics (epistasis); skeletal analysis; in situ hybridization for Hox genes Developmental biology Medium 19833123
2022 Cbx2 acts as an effector of the Lin28b/let-7 heterochronic axis controlling hematopoietic maturation. Juvenile Cbx2-/- hematopoietic tissues show impaired B-lymphopoiesis and a precocious adult-like myeloid bias. Cbx2/PRC1 regulates developmental timing of expression of key hematopoietic transcription factors. Cbx2-/- mouse hematopoietic analysis; transcriptomic data mining; gene regulatory network reconstruction; lineage output analysis Cell reports Medium 35385744
2020 Loss of CBX2 in mouse fibroblasts induces abnormal large-scale chromatin structure, decondensation of satellite DNA sequences at metaphase, increased sister chromatid recombination, and rampant chromosome instability including centromere and telomere defects, demonstrating a role for CBX2 in heterochromatin homeostasis and genome stability. Cbx2-/- mouse fibroblasts; ATAC-seq; transcriptome analysis; cytogenetic analysis; FISH for satellite DNA/telomeres/centromeres The Journal of cell biology High 32870972

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2019 Phase separation of Polycomb-repressive complex 1 is governed by a charged disordered region of CBX2. Genes & development 280 31171700
2018 Nuclear condensates of the Polycomb protein chromobox 2 (CBX2) assemble through phase separation. The Journal of biological chemistry 277 30514760
1998 Male-to-female sex reversal in M33 mutant mice. Nature 241 9641679
1997 Altered cellular proliferation and mesoderm patterning in Polycomb-M33-deficient mice. Development (Cambridge, England) 234 9043087
2002 Murine cytomegalovirus (CMV) M33 and human CMV US28 receptors exhibit similar constitutive signaling activities. Journal of virology 140 12134021
1997 Ring1A is a transcriptional repressor that interacts with the Polycomb-M33 protein and is expressed at rhombomere boundaries in the mouse hindbrain. The EMBO journal 131 9312051
2009 Ovaries and female phenotype in a girl with 46,XY karyotype and mutations in the CBX2 gene. American journal of human genetics 126 19361780
2000 Identification of mu-class glutathione transferases M2-2 and M3-3 as cytosolic prostaglandin E synthases in the human brain. Neurochemical research 76 10905636
2015 Cbx2 targets PRC1 to constitutive heterochromatin in mouse zygotes in a parent-of-origin-dependent manner. Molecular cell 75 25801166
2019 CBX2 Regulates Proliferation and Apoptosis via the Phosphorylation of YAP in Hepatocellular Carcinoma. Journal of Cancer 72 31258779
2009 Additional sex combs-like 1 belongs to the enhancer of trithorax and polycomb group and genetically interacts with Cbx2 in mice. Developmental biology 71 19833123
2018 CBX2 identified as driver of anoikis escape and dissemination in high grade serous ovarian cancer. Oncogenesis 70 30478317
2005 Mouse Polycomb M33 is required for splenic vascular and adrenal gland formation through regulating Ad4BP/SF1 expression. Blood 69 15899914
2016 Identification of the epigenetic reader CBX2 as a potential drug target in advanced prostate cancer. Clinical epigenetics 66 26877821
1998 RAE28, BMI1, and M33 are members of heterogeneous multimeric mammalian Polycomb group complexes. Biochemical and biophysical research communications 65 9571155
2014 Genotranscriptomic meta-analysis of the Polycomb gene CBX2 in human cancers: initial evidence of an oncogenic role. British journal of cancer 64 25225902
2019 Overexpression of CBX2 in breast cancer promotes tumor progression through the PI3K/AKT signaling pathway. American journal of translational research 58 30972192
2019 CBX2 is required to stabilize the testis pathway by repressing Wnt signaling. PLoS genetics 55 31116734
2009 The M33 chemokine receptor homolog of murine cytomegalovirus exhibits a differential tissue-specific role during in vivo replication and latency. Journal of virology 55 19439478
1993 Contribution of glutathione transferase M3-3 to 1,3-bis(2-chloroethyl)-1-nitrosourea resistance in a human non-small cell lung cancer cell line. Cancer research 47 8395980
2000 Altered retinoic acid sensitivity and temporal expression of Hox genes in polycomb-M33-deficient mice. Developmental biology 46 10926763
2007 Functional analysis of the murine cytomegalovirus chemokine receptor homologue M33: ablation of constitutive signaling is associated with an attenuated phenotype in vivo. Journal of virology 45 18057236
2021 A Potent, Selective CBX2 Chromodomain Ligand and Its Cellular Activity During Prostate Cancer Neuroendocrine Differentiation. Chembiochem : a European journal of chemical biology 43 33950564
2021 CBX2 and EZH2 cooperatively promote the growth and metastasis of lung adenocarcinoma. Molecular therapy. Nucleic acids 39 35070495
2018 The HDAC inhibitor SAHA regulates CBX2 stability via a SUMO-triggered ubiquitin-mediated pathway in leukemia. Oncogene 37 29467492
2021 Multiomics integrative analysis reveals antagonistic roles of CBX2 and CBX7 in metabolic reprogramming of breast cancer. Molecular oncology 36 33400401
2005 Mouse cytomegalovirus M33 is necessary and sufficient in virus-induced vascular smooth muscle cell migration. Journal of virology 36 16051870
1994 Co-variation of glutathione transferase expression and cytostatic drug resistance in HeLa cells: establishment of class Mu glutathione transferase M3-3 as the dominating isoenzyme. The Biochemical journal 34 8280111
2011 Additional copies of CBX2 in the genomes of males of mammals lacking SRY, the Amami spiny rat (Tokudaia osimensis) and the Tokunoshima spiny rat (Tokudaia tokunoshimensis). Chromosome research : an international journal on the molecular, supramolecular and evolutionary aspects of chromosome biology 33 21656076
2017 Phosphorylation of CBX2 controls its nucleosome-binding specificity. Journal of biochemistry 32 28992316
2022 CBX2 shapes chromatin accessibility promoting AML via p38 MAPK signaling pathway. Molecular cancer 31 35681235
2019 Beyond EZH2: is the polycomb protein CBX2 an emerging target for anti-cancer therapy? Expert opinion on therapeutic targets 30 31177918
2014 The M33 G protein-coupled receptor encoded by murine cytomegalovirus is dispensable for hematogenous dissemination but is required for growth within the salivary gland. Journal of virology 29 25100846
2014 Cbx2 stably associates with mitotic chromosomes via a PRC2- or PRC1-independent mechanism and is needed for recruiting PRC1 complex to mitotic chromosomes. Molecular biology of the cell 29 25232004
2011 Efficacy and toxicity of the antimicrobial peptide M33 produced with different counter-ions. Amino acids 29 21984381
2019 A novel approach to modelling transcriptional heterogeneity identifies the oncogene candidate CBX2 in invasive breast carcinoma. British journal of cancer 28 30820027
2020 CBX2 depletion inhibits the proliferation, invasion and migration of gastric cancer cells by inactivating the YAP/β-catenin pathway. Molecular medicine reports 27 33313949
2006 G protein-coupled receptor (GPCR) kinase 2 regulates agonist-independent Gq/11 signaling from the mouse cytomegalovirus GPCR M33. The Journal of biological chemistry 27 17088245
2018 Polycomb chromobox Cbx2 enhances antiviral innate immunity by promoting Jmjd3-mediated demethylation of H3K27 at the Ifnb promoter. Protein & cell 26 30357595
2010 Phosphorylation of the chromodomain changes the binding specificity of Cbx2 for methylated histone H3. Biochemical and biophysical research communications 26 20493168
2015 Genome-wide identification of CBX2 targets: insights in the human sex development network. Molecular endocrinology (Baltimore, Md.) 25 25569159
2019 CBX2 is a functional target of miRNA let-7a and acts as a tumor promoter in osteosarcoma. Cancer medicine 24 31150156
2009 Activation of intracellular signaling pathways by the murine cytomegalovirus G protein-coupled receptor M33 occurs via PLC-{beta}/PKC-dependent and -independent mechanisms. Journal of virology 24 19494016
1989 Nucleotide sequence of the 24S subgenomic messenger RNA of a vaccine strain (HPV77) of rubella virus: comparison with a wild-type strain (M33). Gene 24 2583526
2021 Circ_0061140 knockdown inhibits tumorigenesis and improves PTX sensitivity by regulating miR-136/CBX2 axis in ovarian cancer. Journal of ovarian research 23 34649611
2004 Disruption of E2F signaling suppresses the INK4a-induced proliferative defect in M33-deficient mice. Oncogene 23 15377996
2021 CBX2 Induces Glioma Cell Proliferation and Invasion Through the Akt/PI3K Pathway. Technology in cancer research & treatment 22 34709960
2020 Loss of CBX2 induces genome instability and senescence-associated chromosomal rearrangements. The Journal of cell biology 22 32870972
2022 Developmental maturation of the hematopoietic system controlled by a Lin28b-let-7-Cbx2 axis. Cell reports 21 35385744
2022 The Epigenetic Regulatory Protein CBX2 Promotes mTORC1 Signalling and Inhibits DREAM Complex Activity to Drive Breast Cancer Cell Growth. Cancers 21 35884550
2011 Role of polycomb group protein cbx2/m33 in meiosis onset and maintenance of chromosome stability in the Mammalian germline. Genes 21 22200029
2002 Nuclear translocation of mouse polycomb m33 protein in regenerating liver. Biochemical and biophysical research communications 20 11855817
2018 CBX2 Inhibits Neurite Development by Regulating Neuron-Specific Genes Expression. Frontiers in molecular neuroscience 19 29541019
2020 LncRNA PCAT6 promotes the proliferation, migration and invasion of pancreatic ductal adenocarcinoma via regulating miR-185-5p/CBX2 axis. Pathology, research and practice 18 32825947
2019 The transcriptional regulator CBX2 and ovarian function: A whole genome and whole transcriptome approach. Scientific reports 17 31745224
1995 Assignment of a Polycomb-like chromobox gene (CBX2) to human chromosome 17q25. Genomics 17 7782071
2017 Tetraselmis suecica F&M-M33 growth is influenced by its associated bacteria. Microbial biotechnology 16 29105335
2020 Effects of Wnt/β-Catenin Signal Pathway Regulated by miR-342-5p Targeting CBX2 on Proliferation, Metastasis and Invasion of Ovarian Cancer Cells. Cancer management and research 15 32547214
2018 Assembling the jigsaw puzzle: CBX2 isoform 2 and its targets in disorders/differences of sex development. Molecular genetics & genomic medicine 15 29998616
2023 CBX2-mediated suppression of SIAH2 triggers WNK1 accumulations to promote glycolysis in hepatocellular carcinoma. Experimental cell research 14 36780970
2024 CBX2 Deletion Suppresses Growth and Metastasis of Colorectal Cancer by Mettl3-p38/ERK MAPK Signalling Pathway. Journal of Cancer 13 38495501
2020 CASC9 Facilitates Cell Proliferation in Bladder Cancer by Regulating CBX2 Expression. Nephron 13 32570259
2024 USP33 facilitates the ovarian cancer progression via deubiquitinating and stabilizing CBX2. Oncogene 11 39256572
2022 The CMV-encoded G protein-coupled receptors M33 and US28 play pleiotropic roles in immune evasion and alter host T cell responses. Frontiers in immunology 10 36569845
2018 Mouse polycomb group gene Cbx2 promotes osteoblastic but suppresses adipogenic differentiation in postnatal long bones. Bone 10 30389610
2023 The Viral G-Protein-Coupled Receptor Homologs M33 and US28 Promote Cardiac Dysfunction during Murine Cytomegalovirus Infection. Viruses 9 36992420
2021 The Mouse Cytomegalovirus G Protein-Coupled Receptor Homolog, M33, Coordinates Key Features of In Vivo Infection via Distinct Components of Its Signaling Repertoire. Journal of virology 9 34878888
2020 Cytomegalovirus chemokine receptor M33 knockout reduces chronic allograft rejection in a murine aortic transplant model. Transplant immunology 9 33301898
2023 Cell type-specific role of CBX2 and its disordered region in spermatogenesis. Genes & development 8 37553262
2022 CBX2 in DSD: The Quirky Kid on the Block. Sexual development : genetics, molecular biology, evolution, endocrinology, embryology, and pathology of sex determination and differentiation 8 35263754
2012 CBX2 gene analysis in patients with 46,XY and 46,XX gonadal disorders of sex development. Fertility and sterility 8 23219007
1997 Role of O6-methylguanine-DNA methyltransferase, glutathione transferase M3-3 and glutathione in resistance to carmustine in a human non-small cell lung cancer cell line. European journal of cancer (Oxford, England : 1990) 8 9155531
2024 CBX2 enhances the progression and TMZ chemoresistance of glioma via EZH2-mediated epigenetic silencing of PTEN expression. Frontiers in pharmacology 7 39114365
2023 MiR-30a-5p inhibits cell behaviors in esophageal cancer via modulating CBX2. Mutation research 7 37196609
2023 Phosphorylation of USP27X by GSK3β maintains the stability and oncogenic functions of CBX2. Cell death & disease 7 38030604
2022 Cannabidiol promotes apoptosis of osteosarcoma cells in vitro and in vivo by activating the SP1-CBX2 axis. American journal of translational research 7 35273722
2020 Cbx2, a PcG Family Gene, Plays a Regulatory Role in Medaka Gonadal Development. International journal of molecular sciences 7 32075028
2019 CBX2-dependent transcriptional landscape: implications for human sex development and its defects. Scientific reports 7 31719618
2025 CBX2 suppresses interferon signaling to diminish tumor immunogenicity via a noncanonical corepressor complex. Proceedings of the National Academy of Sciences of the United States of America 6 39883845
2024 Cuproptosis-related ceRNA axis triggers cell proliferation and cell cycle through CBX2 in lung adenocarcinoma. BMC pulmonary medicine 6 38355480
2023 Loss of CBX2 causes genomic instability and Wnt activation in high grade serous ovarian carcinoma cells. Molecular carcinogenesis 6 36621979
2023 miR‑149‑3p suppresses the proliferation and metastasis of glioma cells by targeting the CBX2/Wnt/β‑catenin pathway. Experimental and therapeutic medicine 6 37954123
2025 CBX2 promotes cervical cancer cell proliferation and resistance to DNA-damaging treatment via maintaining cancer stemness. The Journal of biological chemistry 5 39793896
2023 Subcellular expression pattern and clinical significance of CBX2 and CBX7 in breast cancer subtypes. Medical molecular morphology 5 37553450
2024 Sparse CBX2 nucleates many Polycomb proteins to promote facultative heterochromatinization of Polycomb target genes. bioRxiv : the preprint server for biology 4 38370615
2021 Role of CMV chemokine receptor M33 in airway graft rejection in a mouse transplant model. Transplant immunology 4 34033867
2016 Characterization of endoglucanase from Paenibacillus sp. M33, a novel isolate from a freshwater swamp forest. Journal of basic microbiology 4 27862076
2021 CBX2 Expression in Colorectal Mucosa-adenoma-adenocarcinoma Sequence. Journal of the College of Physicians and Surgeons--Pakistan : JCPSP 3 34500520
2006 Identification of a nuclear localization signal in mouse polycomb protein, M33. Zoological science 3 17043400
2025 CBX2 as a therapeutic target in colorectal cancer: insights into the altered chromatin accessibility via RUNX1-CBX2-MAP4K1 axis. Oncogene 2 40082555
2025 Identification of substituted acetanilide compounds as small molecule CBX2 inhibitors via in silico screening. Biochemical and biophysical research communications 2 40315569
2023 Spinal CBX2 contributes to neuropathic pain by activating ERK signaling pathway in male mice. Neuroscience letters 2 37422020
2022 cbx2 is a functional target of the let-7 family in the gonad of Japanese flounder (Paralichthys olivaceus). Comparative biochemistry and physiology. Part B, Biochemistry & molecular biology 2 36155820
2025 Antiviral Immune Responses Against Murine Cytomegalovirus Induced by an Oral Salmonella-Based Vaccine Expressing Viral M33 Protein. Microorganisms 1 40732019
2025 CBX2 and EZH2 cooperatively contribute to 5-Fu resistance in gastric cancer by suppressing ferroptosis via trimethylation of H3k27. Cellular signalling 1 40848940
2026 CBX2 promotes cisplatin resistance in ovarian cancer via SIAH2-mediated β-catenin stabilization and ATG9B-dependent autophagy activation. Journal of ovarian research 0 41495834
2026 CBX2 phase-separation contributes to homologous recombination repair and drug resistance in ovarian cancer. Cell death & disease 0 41888115
2026 Epigenetic and ncRNA Regulation of CBX2 in Liver Hepatocellular Carcinoma: A Comprehensive Multi-Omics Analysis for Understanding Biological Significance. Medicina (Kaunas, Lithuania) 0 42195095
2025 CBX2 promoted oral squamous cell carcinoma via increasing CEP55/NF-κB/METTL3/SHP2 signaling induced metastasis/proliferation and angiogenesis. Scientific reports 0 41423460
2021 M33 condenses chromatin through nuclear body formation and methylation of both histone H3 lysine 9 and lysine 27. Biochimica et biophysica acta. Molecular cell research 0 34274396

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