CBX5

Summary

CBX5 (chromobox 5, HGNC:1555) is a protein-coding gene on chromosome 12q13.13, encoding Chromobox protein homolog 5 (P45973). Component of heterochromatin that recognizes and binds histone H3 tails methylated at ‘Lys-9’ (H3K9me), leading to epigenetic repression.

This gene encodes a highly conserved nonhistone protein, which is a member of the heterochromatin protein family. The protein is enriched in the heterochromatin and associated with centromeres. The protein has a single N-terminal chromodomain which can bind to histone proteins via methylated lysine residues, and a C-terminal chromo shadow-domain (CSD) which is responsible for the homodimerization and interaction with a number of chromatin-associated nonhistone proteins. The encoded product is involved in the formation of functional kinetochore through interaction with essential kinetochore proteins. The gene has a pseudogene located on chromosome 3. Multiple alternatively spliced variants, encoding the same protein, have been identified.

Source: NCBI Gene 23468 — RefSeq curated summary.

At a glance

• GWAS associations: 9
• Clinical variants (ClinVar): 17 total
• Druggable target: yes
• MANE Select transcript: NM_012117

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1555
Approved symbol	CBX5
Name	chromobox 5
Location	12q13.13
Locus type	gene with protein product
Status	Approved
Aliases	HP1Hs-alpha, HP1, HP1-ALPHA, HP1alpha
Ensembl gene	ENSG00000094916
Ensembl biotype	protein_coding
OMIM	604478
Entrez	23468

Gene structure

Transcript identifiers

Ensembl transcripts: 28 — 26 protein_coding, 1 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000209875, ENST00000439541, ENST00000547872, ENST00000550411, ENST00000552562, ENST00000618078, ENST00000882084, ENST00000882085, ENST00000882086, ENST00000882087, ENST00000882088, ENST00000882089, ENST00000882090, ENST00000882091, ENST00000882092, ENST00000882093, ENST00000882094, ENST00000882095, ENST00000882096, ENST00000930389, ENST00000930390, ENST00000930391, ENST00000930392, ENST00000930393, ENST00000930394, ENST00000930395, ENST00000930396, ENST00000930397

RefSeq mRNA: 3 — MANE Select: NM_012117 NM_001127321, NM_001127322, NM_012117

CCDS: CCDS8875

Canonical transcript exons

ENST00000209875 — 5 exons

Exon	Start	End
ENSE00000920021	54252041	54252227
ENSE00000920022	54257514	54257692
ENSE00001256276	54230942	54241905
ENSE00002348468	54280008	54280122
ENSE00003467727	54246115	54246215

Expression profiles

Bgee: expression breadth ubiquitous, 290 present calls, max score 99.17.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 76.9902 / max 2065.8091, expressed in 1816 samples.

FANTOM5 promoters (14 alternative TSS)

Promoter ID	TPM avg	Samples expressed
131314	66.1213	1815
131311	7.1198	1195
131313	1.3347	640
131304	0.7843	409
131302	0.4461	212
131301	0.2908	85
131299	0.2362	95
131310	0.1908	72
131298	0.1696	66
131309	0.1235	32

Top tissues by expression

299 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
tendon of biceps brachii	UBERON:0008188	99.17	gold quality
caput epididymis	UBERON:0004358	99.10	gold quality
corpus epididymis	UBERON:0004359	98.42	gold quality
medial globus pallidus	UBERON:0002477	98.01	gold quality
cauda epididymis	UBERON:0004360	97.82	gold quality
globus pallidus	UBERON:0001875	97.46	gold quality
pigmented layer of retina	UBERON:0001782	97.19	gold quality
retina	UBERON:0000966	97.16	gold quality
ventricular zone	UBERON:0003053	96.93	gold quality
mucosa of paranasal sinus	UBERON:0005030	96.62	gold quality
ganglionic eminence	UBERON:0004023	96.37	gold quality
entorhinal cortex	UBERON:0002728	96.16	gold quality
trabecular bone tissue	UBERON:0002483	96.04	gold quality
colonic epithelium	UBERON:0000397	95.76	gold quality
adult organism	UBERON:0007023	95.62	gold quality
embryo	UBERON:0000922	95.49	gold quality
Brodmann (1909) area 23	UBERON:0013554	95.25	gold quality
tendon	UBERON:0000043	95.21	gold quality
postcentral gyrus	UBERON:0002581	95.14	gold quality
pericardium	UBERON:0002407	95.06	gold quality
adrenal tissue	UBERON:0018303	94.87	gold quality
parietal lobe	UBERON:0001872	94.72	gold quality
superior vestibular nucleus	UBERON:0007227	94.50	gold quality
oral cavity	UBERON:0000167	94.26	gold quality
cortical plate	UBERON:0005343	94.24	gold quality
mammary duct	UBERON:0001765	94.03	gold quality
middle temporal gyrus	UBERON:0002771	94.01	gold quality
epithelium of nasopharynx	UBERON:0001951	94.00	gold quality
lateral globus pallidus	UBERON:0002476	93.99	gold quality
nasopharynx	UBERON:0001728	93.98	gold quality

Single-cell (SCXA)

Detected in 9 experiment(s), a significant marker in 8.

Experiment	Marker?	Max mean expression
E-MTAB-7051	yes	4623.21
E-MTAB-6819	yes	963.35
E-MTAB-3929	yes	320.37
E-CURD-112	yes	44.32
E-HCAD-13	yes	19.80
E-MTAB-6678	yes	9.97
E-MTAB-10553	yes	7.17
E-MTAB-9801	no	2.58
E-ANND-3	no	0.00

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

1 targets.

Target	Regulation
MEF2C	Repression

Upstream regulators (CollecTRI, top): CEBPB, E2F1, E2F4, E2F5, E2F6, KMT2A, MYC, NKX3-1, RCOR2, RELB, TAL1, TFAP2A, YY1

miRNA regulators (miRDB)

407 targeting CBX5, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-3925-3P	100.00	69.95	1237
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-6851-5P	100.00	65.63	1294
HSA-MIR-3689D	100.00	66.14	1181
HSA-MIR-4673	100.00	66.64	1490
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-5193	100.00	67.26	1744
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-450A-1-3P	100.00	69.33	1837
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-223-3P	99.99	70.14	1140
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-6759-5P	99.99	66.54	785
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775

Literature-anchored findings (GeneRIF, showing 40)

• These results suggested that, although the majority of HP1alpha diffuses into the cytoplasm, some populations are retained in the centromeric region and involved in the association and segregation of sister kinetochores during mitosis. (PMID:11942629)
• Gene regulation by human orthologs of Drosophila heterochromatin protein 1. (PMID:12054505)
• identification of three amino acid residues I113, A114 and C133 in HP1alpha that are essential for the selective interaction of HP1alpha with BRG1 (PMID:12411497)
• developmentally regulated ARL5, with its distinctive nuclear/nucleolar localization and interaction with HP1alpha, may play a role(s) in nuclear dynamics and/or signaling cascades during embryonic development (PMID:12414990)
• the chromodomain and the chromoshadow domain of HP1 are both required for binding to native chromatin in vivo, but they contribute differentially to binding in euchromatin and heterochromatin (PMID:12560555)
• histone H3 methylase Suv39h1 and the methyl lysine-binding protein HP1alpha directly interact with MBD of MBD1 in vitro and in cells (PMID:12711603)
• cells are exquisitely sensitive to the amount of HP1(Hsalpha) or HP1(Hsbeta) present, as their overexpression influences telomere stability, population doubling time, radioresistance, and tumorigenicity (PMID:14585993)
• HP1 has a role in the recruitment but not in the stable association of Orc1p with heterochromatin (PMID:15454574)
• HP1alpha recruits endogenous HP1beta to the chromatin and this induces heterochromatin formation and enhanced histone lysine methylation. (PMID:15899859)
• Results describe the predominant nuclear localization of another Arp subfamily, Arp6, in vertebrate cells, and show its colocalization with heterochromatin protein 1 orthologs in pericentric heterochromatin. (PMID:16487625)
• modulation of HP1(Hsalpha) alters the invasive potential of breast cancer cells through mechanisms requiring HP1 dimerization (PMID:16648629)
• Phosphorylation of the linker histone H1 by CDK regulates its binding to HP1alpha (PMID:16762841)
• These data indicate that defects in pericentromeric epigenetic heterochromatin modifications initiate a dynamic HP1-dependent response that rescues pericentromeric heterochromatin function and is essential for viable progression through mitosis. (PMID:17101789)
• In non-differentiated cells, transcriptional intermediary factor TIF1beta/heterochromatin protein HP1 interaction occurs only within euchromatin and involves selectively HP1beta and HP1gamma, but not HP1alpha. (PMID:17381543)
• Direct interactions between HP1 and DNMT1 mediate silencing of euchromatic genes. (PMID:17470536)
• HP1-mediated inhibition of preinitiation complex (PIC) assembly in vitro on chromatin templates regulated by GAL4-VP16 or Sp1, is analyzed. (PMID:18264112)
• The histone subcode: poly(ADP-ribose) polymerase-1 (Parp-1) and Parp-2 control cell differentiation by regulating the transcriptional intermediary factor TIF1beta and the heterochromatin protein HP1alpha (PMID:18676401)
• G9a and HP1 couple histone and DNA methylation to TNFalpha transcription silencing during endotoxin tolerance (PMID:18809684)
• results show no evidence for a requirement of HP1 proteins for either loading of bulk cohesin onto chromatin in interphase or retention of cohesin at pericentric heterochromatin in mitosis (PMID:19352502)
• HP1 is recruited to the damaged regions in hetero- as well as euchromatin within a few minutes after damage. (PMID:19479850)
• The histone H3K9 methyltransferase SetDB1 associates with the specific heterochromatin protein 1alpha (HP1alpha)-chromatin assembly factor 1 (CAF1) chaperone complex. (PMID:19498464)
• reduction of YY1 expression in breast cancer cells could contribute to the acquisition of an invasive phenotype through increased cell migration as well as by reduced expression of HP1alpha (PMID:19566924)
• Heterochromatin protein 1 is extensively decorated with histone code-like post-translational modifications (PMID:19567367)
• Data demonstrate that hnRNP U is involved in HP1alpha function, shedding new light on the mode of action of HP1alpha and on the function of hnRNP U. (PMID:19617346)
• Heterochromatin protein 1alpha (HP1alpha), but not HP1beta, specifically binds to Tyr 41 region of H3 through its chromo-shadow domain; phosphorylation of H3Y41 by JAK2 prevents this binding (PMID:19783980)
• data suggest that HP1 chromoshadow-domains can benefit from the opening of nucleosomal structures to bind chromatin and that HP1 proteins use this property to detect and arrest unwanted chromatin remodeling (PMID:20011120)
• HP1alpha expression regulation is dependent on cell proliferation. (PMID:20049717)
• ATRX185 is required for HP1a deposition in pericentric beta-heterochromatin of the X chromosome (PMID:20154359)
• The assembly of HP1 in the inner centromere and the localization of hMis14 at the kinetochore are mutually dependent in human chromosomes. (PMID:20231385)
• Recent findings and controversies concerning HP1 functions in mammalian cells in comparison to studies in other organisms, are reviewed. (PMID:20421743)
• Mislocalized lamins can induce ubiquitin-mediated proteasomal degradation of certain HP1 isoforms by activation of FBXW10, a member of the F-box family of proteins that is involved in E3 ubiquitin ligase activity. (PMID:20498703)
• The results reveal POGZ as an essential protein that links HP1alpha dissociation with Aurora B kinase activation during mitosis. (PMID:20562864)
• we show distinct cell-type- and cancer-stage-associated patterns of key heterochromatin marks: heterochromatic adaptor proteins HP1alpha and HP1gamma, compared with the gammaH2AX marker of endogenously activated DNA damage response. (PMID:20695923)
• HP1alpha binding by INCENP or Shugoshin 1 (Sgo1) is dispensable for centromeric cohesion protection during mitosis of human cells, but might regulate yet unknown interphase functions of the chromosome passenger complex (CPC) or Sgo1 at the centromeres. (PMID:21346195)
• A link between mutant codanin-1 and the aberrant localization of HP1 alpha is supported by the finding that codanin-1 can be coimmunoprecipitated by anti-HP1 alpha antibodies erythroblasts from patients with congenital dyserythropoietic anemia type 1. (PMID:21364188)
• The finding that HP1 alpha is down-regulated primarily at the transcriptional level provides a new insight for the further elucidation of the detailed molecular mechanisms causing the HP1 alpha down-regulation in invasive breast cancer cells. (PMID:21374739)
• HIV-1 Vpr displaces heterochromatin protein 1-alpha and heterochromatin protein 1-gamma from chromatin, resulting in premature chromatid separation. (PMID:21875947)
• HP1-dependent regulation of KAP1 influences DNA repair in heterochromatin. (PMID:22205726)
• HP1 increases the chromatin association of VHL. (PMID:22234250)
• These studies reveal a novel role for HP1 as a cofactor in tumor suppression, expand our mechanistic understanding of a KLF associated to human disease. (PMID:22318730)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	cbx5	ENSDARG00000061187
mus_musculus	Cbx5	ENSMUSG00000009575
rattus_norvegicus	Cbx5	ENSRNOG00000036841
caenorhabditis_elegans		WBGENE00001995
caenorhabditis_elegans		WBGENE00007615

Paralogs (8): CBX7 (ENSG00000100307), CBX1 (ENSG00000108468), CBX3 (ENSG00000122565), CBX8 (ENSG00000141570), CBX4 (ENSG00000141582), CBX2 (ENSG00000173894), CBX6 (ENSG00000183741), NPTXR (ENSG00000221890)

Protein

Protein identifiers

Chromobox protein homolog 5 — P45973 (reviewed: P45973)

Alternative names: Antigen p25, Heterochromatin protein 1 homolog alpha

All UniProt accessions (3): P45973, F8VNY3, V9HWG0

UniProt curated annotations — full annotation on UniProt →

Function. Component of heterochromatin that recognizes and binds histone H3 tails methylated at ‘Lys-9’ (H3K9me), leading to epigenetic repression. In contrast, it is excluded from chromatin when ‘Tyr-41’ of histone H3 is phosphorylated (H3Y41ph). Also recognizes and binds histone H1.4 methylated at ‘Lys-26’ (H1.4K26me). Excluded from chromatin when histone H1.4 is Simultaneously methylated at Lys-26 (H1.4K26me) and phosphorylated at Ser-27 (H1.4S27Ph). May contribute to the association of heterochromatin with the inner nuclear membrane by interactions with the lamin-B receptor (LBR). Involved in the formation of kinetochore through interaction with the MIS12 complex subunit NSL1. Required for the formation of the inner centromere.

Subunit / interactions. Homodimer. Interacts with histone H3 methylated at ‘Lys-9’. Interacts (via Chromo 2; shadow subtype domain) with the MIS12 complex subunit NSL1; the interaction is direct, involves dimeric CBX5, and occurs during interphase. Interacts with POGZ; POGZ and PXVXL motif-containing proteins such as INCENP and TRIM28 compete for interaction with CBX5. Interacts with LRIF1 (via PxVxL motif). Interacts with INCENP. Interacts with TRIM24. Interacts (via the chromoshadow domain) with ATRX; the interaction is direct. Interacts (via the chromoshadow domain) with CHAF1A; the interaction is direct. Interacts (via the chromoshadow domain) with LBR; the interaction is direct. Interacts (via the chromoshadow domain) with NIPBL; the interaction is direct. Interacts (via the chromoshadow domain) with SP100; the interaction is direct. Interacts (via the chromoshadow domain) with STAM2; the interaction is direct. Interacts (via the chromoshadow domain) with TRIM28; the interaction is direct. Interacts (via the chromoshadow domain) with CBX3; the interaction is direct. Interacts with PRR14 (via N-terminus). Interacts with RRP1B. Interacts with HNRNPU (via C-terminus); this interaction is, at least in part, RNA-dependent. Interacts with ZNF263; recruited to the SIX3 promoter along with other proteins involved in chromatin modification and transcriptional corepression where it contributes to transcriptional repression. Interacts with AURKB during mitosis. Interacts with CHAMP1. Interacts with BAHD1. Interacts with HP1BP3. Interacts with CHD3. Interacts with CHD4. Interacts with SMYD5. Interacts with KMT5B. Interacts with KMT5C. Interacts with ASB7 (via PxVxL motif 1); leading to ASB7 recruitment to heterochromatin. (Microbial infection) Interacts with JC virus agnoprotein; this interaction induces the dissociation of CBX5 from LBR, resulting in destabilization of the nuclear envelope.

Subcellular location. Nucleus. Chromosome. Centromere.

Post-translational modifications. Phosphorylation of HP1 and LBR may be responsible for some of the alterations in chromatin organization and nuclear structure which occur at various times during the cell cycle. Phosphorylated during interphase and possibly hyper-phosphorylated during mitosis. Ubiquitinated.

RefSeq proteins (3): NP_001120793, NP_001120794, NP_036249* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000953	Chromo/chromo_shadow_dom	Domain
IPR008251	Chromo_shadow_dom	Domain
IPR016197	Chromo-like_dom_sf	Homologous_superfamily
IPR017984	Chromo_dom_subgr	Domain
IPR023779	Chromodomain_CS	Conserved_site
IPR023780	Chromo_domain	Domain
IPR051219	Heterochromatin_chromo-domain	Family

Pfam: PF00385, PF01393

UniProt features (34 total): modified residue 8, cross-link 6, strand 6, helix 6, mutagenesis site 3, domain 2, chain 1, region of interest 1, compositionally biased region 1

Structure

Experimental structures (PDB)

6 structures.

PDB	Method	Resolution (Å)
3FDT	X-RAY DIFFRACTION	2
9CEA	X-RAY DIFFRACTION	2.15
9CDW	X-RAY DIFFRACTION	2.4
3I3C	X-RAY DIFFRACTION	2.48
9CMT	X-RAY DIFFRACTION	3.17
8UXQ	ELECTRON MICROSCOPY	6.3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P45973-F1	76.14	0.41

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (14): 92, 95, 97, 32, 91, 102, 106, 154, 184, 11, 12, 13, 14, 40

Mutagenesis-validated functional residues (3):

Position	Phenotype
165	no effect on interaction with pogz. abolishes interaction with trim28, chaf1a and nipbl. abolishes interaction with nsl1
173	abolishes interaction with nsl1.
174	abolishes interaction with trim28, chaf1a, nipbl and hp1bp3, fails to localize to centromeres in mitosis. abolishes inte

Function

Pathways and Gene Ontology

Reactome pathways

14 pathways

ID	Pathway
R-HSA-4551638	SUMOylation of chromatin organization proteins
R-HSA-8953750	Transcriptional Regulation by E2F6
R-HSA-983231	Factors involved in megakaryocyte development and platelet production
R-HSA-9843940	Regulation of endogenous retroelements by KRAB-ZFP proteins
R-HSA-109582	Hemostasis
R-HSA-212165	Epigenetic regulation of gene expression
R-HSA-212436	Generic Transcription Pathway
R-HSA-2990846	SUMOylation
R-HSA-3108232	SUMO E3 ligases SUMOylate target proteins
R-HSA-392499	Metabolism of proteins
R-HSA-597592	Post-translational protein modification
R-HSA-73857	RNA Polymerase II Transcription
R-HSA-74160	Gene expression (Transcription)
R-HSA-9842860	Regulation of endogenous retroelements

MSigDB gene sets: 409 (showing top): E2F_Q4, GOBP_CHROMOSOME_ORGANIZATION, E2F_Q4_01, TGCGCANK_UNKNOWN, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, MITSIADES_RESPONSE_TO_APLIDIN_DN, GOBP_CHROMOSOME_CONDENSATION, GOLDRATH_ANTIGEN_RESPONSE, GOBP_NEGATIVE_REGULATION_OF_GENE_EXPRESSION_EPIGENETIC, E2F_Q3, GOBP_PROTEIN_LOCALIZATION_TO_CHROMATIN, MYCMAX_01, LI_WILMS_TUMOR_VS_FETAL_KIDNEY_1_DN, GOBP_PROTEIN_LOCALIZATION_TO_CHROMOSOME

GO Biological Process (8): negative regulation of transcription by RNA polymerase II (GO:0000122), DNA damage response (GO:0006974), chromosome condensation (GO:0030261), heterochromatin formation (GO:0031507), negative regulation of DNA-templated transcription (GO:0045892), heterochromatin organization (GO:0070828), protein localization to heterochromatin (GO:0097355), chromatin organization (GO:0006325)

GO Molecular Function (12): chromatin binding (GO:0003682), protein-macromolecule adaptor activity (GO:0030674), identical protein binding (GO:0042802), histone deacetylase binding (GO:0042826), ribonucleoprotein complex binding (GO:0043021), protein-containing complex binding (GO:0044877), histone H3K9me2/3 reader activity (GO:0062072), DNA-binding transcription factor binding (GO:0140297), histone H1K26me1 reader activity (GO:0160267), histone H1K26me2 reader activity (GO:0160268), protein binding (GO:0005515), histone reader activity (GO:0140566)

GO Cellular Component (18): histone deacetylase complex (GO:0000118), kinetochore (GO:0000776), chromosome, telomeric region (GO:0000781), heterochromatin (GO:0000792), nucleus (GO:0005634), nuclear envelope (GO:0005635), nucleoplasm (GO:0005654), pericentric heterochromatin (GO:0005721), nucleolus (GO:0005730), chromocenter (GO:0010369), transcription repressor complex (GO:0017053), protein-containing complex (GO:0032991), histone methyltransferase complex (GO:0035097), site of DNA damage (GO:0090734), ribonucleoprotein complex (GO:1990904), chromosome, centromeric region (GO:0000775), chromosome (GO:0005694), PML body (GO:0016605)

Reactome top-level categories

Rollup of top-10 pathways:

Category	Pathways
Gene expression (Transcription)	2
SUMO E3 ligases SUMOylate target proteins	1
Generic Transcription Pathway	1
Hemostasis	1
Regulation of endogenous retroelements	1
RNA Polymerase II Transcription	1
Post-translational protein modification	1
SUMOylation	1
Metabolism of proteins	1
Epigenetic regulation of gene expression	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
intracellular membraneless organelle	4
binding	3
protein binding	2
histone H1 reader activity	2
nucleoplasm	2
nuclear protein-containing complex	2
chromosomal region	2
nuclear lumen	2
cellular anatomical structure	2
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
negative regulation of DNA-templated transcription	1
cellular response to stress	1
chromosome organization	1
cellular component assembly	1
heterochromatin boundary formation	1
negative regulation of gene expression, epigenetic	1
heterochromatin organization	1
DNA-templated transcription	1
regulation of DNA-templated transcription	1
negative regulation of RNA biosynthetic process	1
chromatin organization	1
protein localization to chromatin	1
cellular component organization	1
molecular adaptor activity	1
enzyme binding	1
protein-containing complex binding	1
histone H3 reader activity	1
transcription factor binding	1
nucleosome	1
histone binding	1
chromatin-protein adaptor activity	1
catalytic complex	1
condensed chromosome, centromeric region	1
supramolecular complex	1
chromatin	1
intracellular membrane-bounded organelle	1
nucleus	1
endomembrane system	1
organelle envelope	1

Protein interactions and networks

STRING

2364 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CBX5	H3-3A	P06351	996
CBX5	H3C1	P02295	995
CBX5	H3-4	Q16695	995
CBX5	H3-7	Q5TEC6	995
CBX5	H3-5	Q6NXT2	995
CBX5	H3C14	Q71DI3	995
CBX5	SUV39H1	O43463	994
CBX5	TRIM28	Q13263	973
CBX5	SETDB1	Q15047	971
CBX5	LBR	Q14739	899
CBX5	DSN1	Q9H410	888
CBX5	WRN	Q14191	848
CBX5	DNMT1	P26358	841
CBX5	CBX3	Q13185	810
CBX5	NSL1	Q96IY1	810

IntAct

375 interactions, top by confidence:

A	B	Type	Score
SUV39H1	CBX5	psi-mi:“MI:0914”(association)	0.950
SUV39H1	CBX5	psi-mi:“MI:0915”(physical association)	0.950
CBX5	SUV39H1	psi-mi:“MI:0915”(physical association)	0.950
CBX5	PRR14	psi-mi:“MI:0915”(physical association)	0.920
TRIM28	CBX5	psi-mi:“MI:0915”(physical association)	0.910
DSN1	ZWINT	psi-mi:“MI:0914”(association)	0.900
CBX5	LRIF1	psi-mi:“MI:0915”(physical association)	0.870
LRIF1	CBX5	psi-mi:“MI:0915”(physical association)	0.870
CDK8	MED19	psi-mi:“MI:0914”(association)	0.850
INCENP	CBX5	psi-mi:“MI:0915”(physical association)	0.800
CBX5	INCENP	psi-mi:“MI:0915”(physical association)	0.800
INCENP	CBX5	psi-mi:“MI:0403”(colocalization)	0.800
INCENP	CBX5	psi-mi:“MI:0914”(association)	0.800
CBX5	NSL1	psi-mi:“MI:0915”(physical association)	0.800
PRR14	PPP2R1A	psi-mi:“MI:0914”(association)	0.790
POGZ	CBX5	psi-mi:“MI:0914”(association)	0.780

BioGRID (686): CBX5 (Two-hybrid), CBX5 (Two-hybrid), VPS28 (Two-hybrid), WHSC1L1 (Two-hybrid), SUV39H2 (Two-hybrid), GOLGA8EP (Two-hybrid), CBX5 (Affinity Capture-Western), CBX5 (Affinity Capture-Western), UBE2A (Affinity Capture-Western), UBE2B (Affinity Capture-Western), UBE2A (Co-localization), UBE2B (Co-localization), CBX5 (Co-localization), CBX5 (Affinity Capture-Western), CBX5 (Affinity Capture-Western)

ESM2 similar proteins: A0A286Y9D1, C8VBH4, F4IV99, G5EDE2, G5EET5, J9VQZ0, J9VW97, O13736, O14026, O94880, O97159, P05205, P0CP02, P0CP03, P23198, P29227, P40381, P45968, P45973, P83916, P83917, Q01491, Q10175, Q10251, Q10267, Q13185, Q19972, Q1DU03, Q1MTR4, Q2H988, Q2UTN6, Q4IB50, Q4P3S3, Q4WTT2, Q5ASA5, Q5R6X7, Q61686, Q6C5G5, Q6C9M9, Q6CND0

Diamond homologs: A0A0P0VUY4, B1Q3J6, C0SQ89, D4ZX35, G5EDE2, G5EET5, J9VQZ0, O23273, O33481, O49139, P13864, P23198, P23737, P25265, P26358, P31033, P45973, P50196, P94147, Q13185, Q24K09, Q27746, Q57983, Q5KQL9, Q5R6X7, Q61686, Q7JXA8, Q7Y1I7, Q8LPU5, Q92072, Q94F87, Q94F88, Q99549, Q9ARI6, Q9AXT8, Q9M0S8, G3V8T1, O60016, O95931, P05205

SIGNOR signaling

14 interactions.

A	Effect	B	Mechanism
CSNK2A1	up-regulates	CBX5	phosphorylation
E2F5	“down-regulates quantity by repression”	CBX5	“transcriptional regulation”
POGZ	“down-regulates activity”	CBX5	binding
CBX5	“up-regulates activity”	H3-3A	binding
CBX5	“up-regulates activity”	H3-4	binding
CBX5	“up-regulates activity”	H3C1	binding
CBX5	“up-regulates activity”	“Histone H3”	binding
ASXL3	“down-regulates activity”	CBX5	binding
FBXW10	“down-regulates quantity by destabilization”	CBX5	binding
“Cullin 1-RBX1-Skp1”	“down-regulates quantity by destabilization”	CBX5	polyubiquitination
RNF123	“down-regulates quantity by destabilization”	CBX5	polyubiquitination

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 125 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Amplification of signal from unattached kinetochores via a MAD2 inhibitory signal	7	10.6×	1e-03
PKMTs methylate histone lysines	5	10.4×	6e-03
Differentiation of naive CD4+ T cells to T helper 2 cells (Th2 cells)	5	9.5×	8e-03
EML4 and NUDC in mitotic spindle formation	7	8.4×	3e-03
Regulation of endogenous retroelements by KRAB-ZFP proteins	6	8.3×	5e-03
Mitotic Prometaphase	9	8.1×	9e-04
Resolution of Sister Chromatid Cohesion	7	7.9×	3e-03
RHO GTPases Activate Formins	7	7.1×	4e-03

GO biological processes:

GO term	Partners	Fold	FDR
heterochromatin formation	6	14.1×	9e-04
chromatin organization	11	10.0×	1e-05
chromosome segregation	6	9.6×	5e-03
nucleosome assembly	7	9.0×	2e-03
chromatin remodeling	11	7.4×	1e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

17 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	1
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1349 predictions. Top by Δscore:

Variant	Effect	Δscore
12:54241746:T:TA	donor_gain	1.0000
12:54241748:C:A	donor_gain	1.0000
12:54241751:T:A	donor_gain	1.0000
12:54241758:G:C	donor_gain	1.0000
12:54241775:T:A	donor_gain	1.0000
12:54246211:CTCTG:C	acceptor_gain	1.0000
12:54246213:CTG:C	acceptor_gain	1.0000
12:54246216:C:CC	acceptor_gain	1.0000
12:54252035:GCTTA:G	donor_loss	1.0000
12:54252036:CTTA:C	donor_loss	1.0000
12:54252037:TTAC:T	donor_loss	1.0000
12:54252038:TA:T	donor_loss	1.0000
12:54252040:C:CG	donor_loss	1.0000
12:54252040:CCT:C	donor_gain	1.0000
12:54252040:CCTCT:C	donor_gain	1.0000
12:54252224:CTCC:C	acceptor_gain	1.0000
12:54252226:CC:C	acceptor_gain	1.0000
12:54252227:CC:C	acceptor_gain	1.0000
12:54252228:C:CC	acceptor_gain	1.0000
12:54252228:C:G	acceptor_loss	1.0000
12:54252228:C:T	acceptor_gain	1.0000
12:54252229:T:A	acceptor_loss	1.0000
12:54257507:AACTT:A	donor_loss	1.0000
12:54257508:ACTTA:A	donor_loss	1.0000
12:54257510:TTACT:T	donor_loss	1.0000
12:54257511:TA:T	donor_loss	1.0000
12:54257512:A:AC	donor_gain	1.0000
12:54257512:A:T	donor_loss	1.0000
12:54257512:ACT:A	donor_gain	1.0000
12:54257513:C:CT	donor_gain	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000095385 (12:54246496 G>A,T), RS1000150733 (12:54233759 T>C), RS1000264281 (12:54241046 G>T), RS1000353290 (12:54253531 A>G), RS1000374677 (12:54233993 C>A,G), RS1000481889 (12:54277174 A>C,G), RS1000548290 (12:54265182 T>C), RS1000597628 (12:54236808 C>CG), RS1000611581 (12:54257268 A>G,T), RS1000645742 (12:54258436 T>C,G), RS1000651475 (12:54237149 C>T), RS1000686811 (12:54249514 T>C), RS1000758696 (12:54243424 G>A), RS1000839081 (12:54268322 T>C), RS1000858255 (12:54251984 T>C)

Disease associations

OMIM: gene MIM:604478 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

9 associations (top):

Study	Trait	p-value
GCST001335_22	Mean platelet volume	2.000000e-14
GCST005962_20	Waist-to-hip ratio adjusted for BMI x sex x age interaction (4df test)	7.000000e-13
GCST008162_11	Hip circumference	2.000000e-06
GCST008757_49	Alcohol consumption	8.000000e-11
GCST010002_217	Refractive error	6.000000e-174
GCST010143_26	Meat-related diet	2.000000e-09
GCST010988_494	Adult body size	2.000000e-11
GCST90000047_181	Age at first sexual intercourse	1.000000e-08
GCST90002402_380	Platelet count	2.000000e-10

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0008007	age at assessment
EFO:0008343	sex interaction measurement
EFO:0008111	diet measurement
EFO:0009749	age at first sexual intercourse measurement
EFO:0004309	platelet count

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3826867 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

ChEMBL bioactivities

1 potent at pChembl≥5 of 10 total, top 1 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
5.16	IC50	6900	nM	CHEMBL3935965

PubChem BioAssay actives

1 with measured affinity, of 50 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
methyl (2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-benzamido-3-phenylpropanoyl]amino]propanoyl]amino]-4-methylpentanoyl]amino]-6-(diethylamino)hexanoyl]amino]-3-hydroxypropanoate	1319520: Antagonist activity at recombinant human N-terminal His-tagged CBX5 chromodomain (18 to 75 residues) expressed in Escherichia coli Rosetta BL21(DE3)pLysS using ARTKQTARK(Me3)STGGKAPRKQL-K(Biotin)-NH2 measured after 30 mins by AlphaScreen assay	ic50	6.9000	uM

CTD chemical–gene interactions

71 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, decreases expression	7
sodium arsenite	affects binding, increases reaction, decreases expression, increases expression	5
trichostatin A	affects cotreatment, decreases expression	3
cobaltous chloride	decreases expression	2
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression, decreases expression	2
Vorinostat	decreases expression, increases expression	2
Benzo(a)pyrene	increases expression, increases methylation	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Tretinoin	decreases expression	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	2
p-Chloromercuribenzoic Acid	affects cotreatment, decreases expression	2
GSK-J4	decreases expression	1
FR900359	affects phosphorylation	1
TAK-243	decreases sumoylation	1
testosterone enanthate	affects expression	1
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	decreases expression	1
methylparaben	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
butyraldehyde	decreases expression	1
phenethyl isothiocyanate	decreases expression	1
entinostat	decreases expression	1
bisphenol B	increases expression	1
abrine	decreases expression	1
dorsomorphin	decreases expression, affects cotreatment	1
bisphenol S	increases expression	1
jinfukang	affects cotreatment, decreases expression	1
bis-N,N-dimethylamino-2-(N-methylpyrrolyl)methyl cyclopentadienyl titanium (IV)	decreases expression	1
LDN 193189	increases expression, affects cotreatment	1

ChEMBL screening assays

4 unique, capped per target: 4 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3829394	Binding	Binding affinity to 15N-labeled CBX5ChD (18 to 75 residues) (unknown origin) expressed in RIPL-BL21 (DE3)-CodonPlus competent cells at 200 uM by 1H-15N HSQC NMR spectroscopy	Structure-Guided Discovery of Selective Antagonists for the Chromodomain of Polycomb Repressive Protein CBX7. — ACS Med Chem Lett

Cellosaurus cell lines

9 cell lines: 9 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_D1VK	Abcam A-549 CBX5 KO	Cancer cell line	Male
CVCL_D2A5	Abcam HCT 116 CBX5 KO	Cancer cell line	Male
CVCL_E4KT	ICC21	Cancer cell line	Female
CVCL_SH12	HAP1 CBX5 (-) 1	Cancer cell line	Male
CVCL_SH13	HAP1 CBX5 (-) 2	Cancer cell line	Male
CVCL_SH14	HAP1 CBX5 (-) 3	Cancer cell line	Male
CVCL_SH15	HAP1 CBX5 (-) 4	Cancer cell line	Male
CVCL_SH16	HAP1 CBX5 (-) 5	Cancer cell line	Male
CVCL_SH17	HAP1 CBX5 (-) 6	Cancer cell line	Male

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.