RNF2

Summary

RNF2 (ring finger protein 2, HGNC:10061) is a protein-coding gene on chromosome 1q25.3, encoding E3 ubiquitin-protein ligase RING2 (Q99496). E3 ubiquitin-protein ligase that mediates monoubiquitination of ‘Lys-119’ of histone H2A (H2AK119Ub), thereby playing a central role in histone code and gene regulation. In precision oncology, BAP1 Mutation confers sensitivity to Olaparib in Malignant Mesothelioma (CIViC Level B); 8 further curated variant–drug associations are listed below.

Polycomb group (PcG) of proteins form the multiprotein complexes that are important for the transcription repression of various genes involved in development and cell proliferation. The protein encoded by this gene is one of the PcG proteins. It has been shown to interact with, and suppress the activity of, transcription factor CP2 (TFCP2/CP2). Studies of the mouse counterpart suggested the involvement of this gene in the specification of anterior-posterior axis, as well as in cell proliferation in early development. This protein was also found to interact with huntingtin interacting protein 2 (HIP2), an ubiquitin-conjugating enzyme, and possess ubiquitin ligase activity.

Source: NCBI Gene 6045 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Luo-Schoch-Yamamoto syndrome (Strong, GenCC)
• GWAS associations: 4
• Clinical variants (ClinVar): 48 total — 1 pathogenic
• Phenotypes (HPO): 35
• Druggable target: yes
• Precision-oncology evidence (CIViC): 9 curated variant–drug associations
• Cancer driver (intOGen): loss-of-function (tumor-suppressor-like) across 14 cancer types
• Transcription factor: yes — 17 downstream targets (CollecTRI)
• MANE Select transcript: NM_007212

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:10061
Approved symbol	RNF2
Name	ring finger protein 2
Location	1q25.3
Locus type	gene with protein product
Status	Approved
Aliases	BAP-1, BAP1, DING, HIPI3, RING1B, RING2
Ensembl gene	ENSG00000121481
Ensembl biotype	protein_coding
OMIM	608985
Entrez	6045

Gene structure

Transcript identifiers

Ensembl transcripts: 16 — 15 protein_coding, 1 retained_intron

ENST00000367509, ENST00000367510, ENST00000453650, ENST00000498201, ENST00000715230, ENST00000910311, ENST00000910312, ENST00000910313, ENST00000910314, ENST00000910315, ENST00000925207, ENST00000925208, ENST00000925209, ENST00000925210, ENST00000942958, ENST00000942959

RefSeq mRNA: 1 — MANE Select: NM_007212 NM_007212

CCDS: CCDS1365

Canonical transcript exons

ENST00000367510 — 7 exons

Exon	Start	End
ENSE00000822928	185091579	185091739
ENSE00000822929	185093061	185093276
ENSE00000822931	185099791	185099962
ENSE00001030494	185100200	185102603
ENSE00003685196	185087552	185087640
ENSE00003784417	185098072	185098344
ENSE00004026246	185045558	185045649

Expression profiles

Bgee: expression breadth ubiquitous, 178 present calls, max score 95.43.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 31.3616 / max 344.8437, expressed in 1815 samples.

FANTOM5 promoters (9 alternative TSS)

Promoter ID	TPM avg	Samples expressed
7238	17.0221	1777
7236	6.6053	1737
7237	2.2253	1287
7235	1.6465	1115
7239	1.2580	642
7234	0.9622	686
7233	0.8695	593
7240	0.5574	257
201846	0.2152	87

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	95.43	gold quality
cortical plate	UBERON:0005343	93.40	gold quality
ganglionic eminence	UBERON:0004023	92.71	gold quality
ventricular zone	UBERON:0003053	89.92	gold quality
islet of Langerhans	UBERON:0000006	88.17	gold quality
stromal cell of endometrium	CL:0002255	87.16	gold quality
adrenal tissue	UBERON:0018303	87.16	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	86.45	gold quality
monocyte	CL:0000576	86.15	gold quality
leukocyte	CL:0000738	85.50	gold quality
mononuclear cell	CL:0000842	85.40	gold quality
calcaneal tendon	UBERON:0003701	84.37	gold quality
colonic epithelium	UBERON:0000397	83.70	gold quality
buccal mucosa cell	CL:0002336	83.38	silver quality
embryo	UBERON:0000922	83.32	gold quality
hindlimb stylopod muscle	UBERON:0004252	81.96	gold quality
pancreas	UBERON:0001264	81.61	gold quality
rectum	UBERON:0001052	81.43	gold quality
tendon	UBERON:0000043	81.35	gold quality
gall bladder	UBERON:0002110	80.57	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	80.04	gold quality
omental fat pad	UBERON:0010414	79.99	gold quality
peritoneum	UBERON:0002358	79.95	gold quality
prefrontal cortex	UBERON:0000451	79.63	gold quality
adipose tissue of abdominal region	UBERON:0007808	79.50	gold quality
bone marrow cell	CL:0002092	79.48	gold quality
granulocyte	CL:0000094	79.47	gold quality
left adrenal gland	UBERON:0001234	79.22	gold quality
ectocervix	UBERON:0012249	79.22	gold quality
right testis	UBERON:0004534	79.19	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.98

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

17 targets.

Target	Regulation
BAP1
CASP1
CBX2
COX7C
CP
CXCL8
DLD
FEZF2	Repression
HBA1
HOXB9
MEIS1	Repression
MEIS2	Repression
PC
PRKN
SCNN1A
STRA8
UBC

Upstream regulators (CollecTRI, top): E2F1

miRNA regulators (miRDB)

185 targeting RNF2, 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-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-2110	99.96	66.68	1930
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-3912-5P	99.95	66.11	925
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-3143	99.93	71.96	3104

Literature-anchored findings (GeneRIF, showing 40)

• The human PcG protein dinG interacts with CP2, a mammalian member of the grainyhead-like family of transcription factors, in vitro and in vivo. The functional consequence of this interaction is repression of CP2-dependent transcription. (PMID:11865070)
• The E3 ubiquitin ligase RNF2 might have a dual function: facilitating the ubiquitination of its target substrates and recruiting the substrates to the proteasome. (PMID:15773819)
• Altered mRNA expression is associated with therapy failure and death in patients with multiple types of cancer. (PMID:15931389)
• Bmi-1-Ring1B complex stabilizes the interaction of the ubiquitin ligase complex. (PMID:16714294)
• Ring1B and Bmi1 are degraded by an exogenous E3, independent of their RING domain. The RING domains of both proteins mediate their association and subsequent stabilization. (PMID:17157253)
• caspases-3 and caspase-9 play novel roles in transcription by regulating polycomb protein function through direct cleaving of Ring1B. (PMID:17379327)
• With prohibitin, regulates the activity of E2F1 transcription factor via dual pathways. (PMID:17873902)
• Results show that a phosphorylated form of Mel-18 targets the Ring1B histone H2A ubiquitin ligase to chromatin. (PMID:17936708)
• Data show that the presence of flexible regions could allow C-terminal region of RING1B to bind a variety of different factors, ultimately recruiting RING1B and its associated PcG proteins to different genomic loci. (PMID:18616292)
• a novel mechanism by which RNF2 and PHB2 modulate the CP2-mediated transcriptional pathway. (PMID:18629613)
• Studies in mammalian cells have found a multiplicity of protein complexes containing Ring1A and Ring1B, suggesting an expanded regulatory role for Ring1A, Ring1B proteins in the epigenetic regulation of gene expression. (PMID:19412891)
• Ring1B plays an important role in the induction of T helper (Th)2 cell-driven allergic airway inflammation through the control of Bim-dependent apoptosis of effector T helper (Th)2 cells in vivo. (PMID:20237291)
• polycomb protein Ring1B regulation by self-ubiquitination or by E6-AP may have implications to the pathogenesis of Angelman syndrome (PMID:20351251)
• Polycomb Group protein targeting to different chromatin locations relies, in part, on binding partners of the C-terminal domain of RING1B that are diverse in sequence and structure. (PMID:20696397)
• identification of genes regulated by ring finger protein 2 (PMID:21347701)
• Crystallography of a complex of the Bmi1/Ring1b RING-RING heterodimer & UbcH5c shows that UbcH5c interacts with Ring1b only. Bmi1/Ring1b interacts with nucleosomal DNA & an acidic patch on histone H4 to achieve specific monoubiquitination of H2A. (PMID:21772249)
• the reduction of LPS-mediated IL-8 promoter activation was not related to de novo X-DING-CD4 protein synthesis, but depended on function of the exogenous X-DING-CD4 protein. (PMID:22031506)
• These data provide evidence that the X-DING-CD4 gene contributes to early cellular protection from HIV infection in some individuals and this protection depends solely on the unique genetic regulation of the host. (PMID:22042911)
• The organism reacts to HIV-infection by an overexpression of DING proteins. (PMID:22427948)
• knockdown of RNF2 significantly inhibits both cell proliferation and colony formation and induces apoptosis in cancer cells (PMID:23318437)
• Results indicate that RNF2 is an E3 ligase for p53 degradation in selective cells, implicating RNF2 as a therapeutic target to restore tumor suppression through p53 in certain tumor cells. (PMID:23319651)
• Ring2 may effect the DNA repair through other pathways but not through the expressions of NER protein. (PMID:23712474)
• BMI-1 and RING1B expression was enhanced with the development of embryos in early pregnancy. (PMID:23727134)
• Expressed the isolated N-terminal region of Ring1B, N-Ring1B, comprising the first 221 residues of the 334-residue-long Ring1B and found that the N-Ring1B is a well-folded, monomeric fragment, with native-like structure which unfolds irreversibly. (PMID:24284202)
• The acidic patch functions within the nucleosome as nucleosomes containing a mutated acidic patch exhibit defective H2A/H2AXub by RNF168 and RING1B/BMI1 in vitro (PMID:24603765)
• Bmi1 and possibly RNF2 may be attractive biomarkers of gemcitabine resistance in the context of RRM1 expression. (PMID:24614341)
• we identify p63 as a target of Ring1B to regulate Fak expression in breast cancer epithelial cells (PMID:24742605)
• Data indicate that RING finger protein 2 (RNF2) knockdown can increase the sensitivity of U87 cells to X ray radiation. (PMID:24796740)
• Authors describe a critical role for the polycomb group protein Ring1b in nonhomologous end-joining (NHEJ)-mediated end-to-end chromosome fusions. (PMID:24813883)
• Ring1B and the SNAG-associated chromatin modifier EZH2 formed distinct protein complexes with Snail and that EZH2 was required for Snail-Ring1A/B recruitment to the target promoter. (PMID:24903147)
• combinatorial silencing along with Ezh2 depleted epigenetically modified H2- and H3-histones and inhibited pancreatic cancer cell growth in vitro and in vivo (xenograft model) (PMID:25431952)
• BAP1 deficiency causes increased expression of FoxK2 target genes in a Ring1B-Bmi1-dependent manner (PMID:25451922)
• O-GlcNAc modifies and regulates an essential epigenetic tool, RING1B, which may contribute to human embryonic stem cells pluripotency maintenance and differentiation. (PMID:26100231)
• The enzymatic activity of BMI1 and RING1B were evaluated and compared. (PMID:26151332)
• Our findings support the notion that epigenetic regulators, such as RNF2, directly and functionally control powerful gene networks that are vital in multiple cancer processes. (PMID:26450788)
• overexpression of RNF2, as examined by immunohistochemical analysis, might serve as a novel prognostic biomarker and potential therapeutic target for urothelial carcinoma of the bladder patients. (PMID:26869491)
• Study detected RNF2 expression to be overexpressed in esophageal carcinoma cell lines and was associated with the poor prognosis of esophageal carcinoma patients. Data also reflect its important role in the growth of esophageal carcinoma cells by shRNA silencing of RNF2 expression. (PMID:26936624)
• Our findings identify RING1B as a trait of the cell-of-origin in Ewing sarcoma (PMID:27317769)
• These data suggest that RNF2 is an important upstream negative regulator of SIK1 and that restoration of SIK1 levels induced by loss of RNF2 inhibited HCC cell growth and promoted apoptosis, which may represent a promising therapeutic strategy for HCC treatment. (PMID:27911266)
• Study found that prostate cancer (PCa) tissues have high RNF2 expression which is positively correlated with tumor grade indicating that RNF2 may have oncogenic function in PCa. (PMID:28029659)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	rnf2	ENSDARG00000010381
mus_musculus	Rnf2	ENSMUSG00000026484
rattus_norvegicus	Rnf2	ENSRNOG00000002454
drosophila_melanogaster	Psc	FBGN0005624
drosophila_melanogaster	Su(z)2	FBGN0265623

Paralogs (7): PCGF1 (ENSG00000115289), PCGF6 (ENSG00000156374), BMI1 (ENSG00000168283), PCGF5 (ENSG00000180628), PCGF3 (ENSG00000185619), RING1 (ENSG00000204227), PCGF2 (ENSG00000277258)

Protein

Protein identifiers

E3 ubiquitin-protein ligase RING2 — Q99496 (reviewed: Q99496)

Alternative names: Huntingtin-interacting protein 2-interacting protein 3, Protein DinG, RING finger protein 1B, RING finger protein 2, RING finger protein BAP-1, RING-type E3 ubiquitin transferase RING2

All UniProt accessions (2): Q99496, X6RFN3

UniProt curated annotations — full annotation on UniProt →

Function. E3 ubiquitin-protein ligase that mediates monoubiquitination of ‘Lys-119’ of histone H2A (H2AK119Ub), thereby playing a central role in histone code and gene regulation. H2AK119Ub gives a specific tag for epigenetic transcriptional repression and participates in X chromosome inactivation of female mammals. May be involved in the initiation of both imprinted and random X inactivation. Essential component of a Polycomb group (PcG) multiprotein PRC1-like complex, a complex class required to maintain the transcriptionally repressive state of many genes, including Hox genes, throughout development. PcG PRC1 complex acts via chromatin remodeling and modification of histones, rendering chromatin heritably changed in its expressibility. E3 ubiquitin-protein ligase activity is enhanced by BMI1/PCGF4. Acts as the main E3 ubiquitin ligase on histone H2A of the PRC1 complex, while RING1 may rather act as a modulator of RNF2/RING2 activity. Association with the chromosomal DNA is cell-cycle dependent. In resting B- and T-lymphocytes, interaction with AURKB leads to block its activity, thereby maintaining transcription in resting lymphocytes. Also acts as a negative regulator of autophagy by mediating ubiquitination of AMBRA1, leading to its subsequent degradation.

Subunit / interactions. Component of chromatin-associated Polycomb (PcG) complexes. Component of a number of PRC1-like complexes; these complexes contain either the polycomb group ring finger protein PCGF1, or PCGF2, or PCGF3, or PCGF4, or PCGF5, or PCGF6. Part of a complex that contains RNF2, UB2D3 and BMI1; within that complex RNF2 and BMI1 form a tight heterodimer, where UB2D3 interacts only with RNF2. The complex composed of RNF2, UB2D3 and BMI1 binds nucleosomes, and has activity only with nucleosomal histone H2A. Part of a complex that contains PCGF5, RNF2 and UBE2D3. Part of a complex that contains AUTS2, PCGF5, RNF2, CSNK2B and RYBP. Interacts with RYBP, PCGF2, CBX4, CBX6, CBX7 and CBX8. Interacts with RNF1/RING1, BMI1 and PHC2. Interaction with RYBP and CBX7 is mutually exclusive; both compete for the same binding site on RNF2. Component of repressive BCOR complex containing a Polycomb group subcomplex at least composed of RYBP, PCGF1, BCOR and RING1. Interacts with CBX2 and PHC1. Interacts with CHTOP. Interacts with AURKB. Part of the E2F6.com-1 complex in G0 phase composed of E2F6, MGA, MAX, TFDP1, CBX3, BAT8, EUHMTASE1, RNF1/RING1, RNF2/RING2, MBLR, L3MBTL2 and YAF2. Component of some MLL1/MLL complex, at least composed of the core components KMT2A/MLL1, ASH2L, HCFC1/HCF1, WDR5 and RBBP5, as well as the facultative components BACC1, CHD8, E2F6, HSP70, INO80C, KANSL1, LAS1L, MAX, MCRS1, MGA, MYST1/MOF, PELP1, PHF20, PRP31, RING2, RUVB1/TIP49A, RUVB2/TIP49B, SENP3, TAF1, TAF4, TAF6, TAF7, TAF9 and TEX10. Interacts with RYBP, HIP2 and TFCP2. Interacts with NUPR1. Interacts with SAMD7 in a PHC2-dependent manner.

Subcellular location. Nucleus. Cytoplasm. Chromosome.

Post-translational modifications. Monoubiquitinated, by auto-ubiquitination. Polyubiquitinated in the presence of UBE2D3 (in vitro).

Disease relevance. Luo-Schoch-Yamamoto syndrome (LUSYAM) [MIM:619460] An autosomal dominant disorder characterized by intrauterine growth retardation, severe intellectual disability, behavioral problems, early-onset seizures, feeding difficulties, and dysmorphic features. White matter abnormalities and delayed myelination are observed on brain imaging. The disease is caused by variants affecting the gene represented in this entry.

Pathway. Protein modification; protein ubiquitination.

Miscellaneous. The hPRC-H complex purification reported probably presents a mixture of different PRC1-like complexes.

Isoforms (2)

UniProt ID	Names	Canonical?
Q99496-1	1	yes
Q99496-2	2

RefSeq proteins (1): NP_009143* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001841	Znf_RING	Domain
IPR013083	Znf_RING/FYVE/PHD	Homologous_superfamily
IPR017907	Znf_RING_CS	Conserved_site
IPR032443	RAWUL	Domain
IPR037937	RING2_RAWUL_dom	Domain
IPR043540	RING1/RING2	Family

Pfam: PF13923, PF16207

Enzyme classification (BRENDA):

• EC 2.3.2.27 — RING-type E3 ubiquitin transferase (BRENDA: 28 organisms, 138 substrates, 10 inhibitors, 1 Km, 1 kcat entries)

Substrate kinetics (BRENDA)

1 substrates with measured Km, best-characterized 1. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
[UBE2W]-S-UBIQUITINYL-L-CYSTEINE	0.3014	1

UniProt features (59 total): mutagenesis site 15, helix 11, strand 11, turn 5, modified residue 4, cross-link 3, region of interest 3, sequence variant 2, initiator methionine 1, chain 1, splice variant 1, zinc finger region 1, compositionally biased region 1

Structure

Experimental structures (PDB)

15 structures.

PDB	Method	Resolution (Å)
3GS2	X-RAY DIFFRACTION	1.7
3IXS	X-RAY DIFFRACTION	1.7
6WI7	X-RAY DIFFRACTION	1.7
3H8H	X-RAY DIFFRACTION	2
4S3O	X-RAY DIFFRACTION	2
2H0D	X-RAY DIFFRACTION	2.5
3RPG	X-RAY DIFFRACTION	2.65
9DBY	ELECTRON MICROSCOPY	2.8
8PP7	ELECTRON MICROSCOPY	2.91
9DGG	ELECTRON MICROSCOPY	2.98
8GRM	ELECTRON MICROSCOPY	3.05
6WI8	X-RAY DIFFRACTION	3.09
9DDE	ELECTRON MICROSCOPY	3.2
4R8P	X-RAY DIFFRACTION	3.28
7ND1	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q99496-F1	78.27	0.44

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 (7): 168, 112, 249, 323, 2, 41, 143

Mutagenesis-validated functional residues (15):

Position	Phenotype
41	no effect on ubiquitin ligase activity on histone h2a.
51	strong decrease in hip2-binding; when associated with s-54.
54	strong decrease in hip2-binding; when associated with w-51.
56	loss of ubiquitin ligase activity on histone h2a.
69	loss of hip2-binding and loss of ubiquitin ligase activity on histone h2a.
70	loss of ubiquitin ligase activity on histone h2a.
81	decreases ubiquitin ligase activity on histone h2a.
93	mildly decreases ubiquitin ligase activity on histone h2a.
97–98	loss of ubiquitin ligase activity on histone h2a.
97	strongly decreases ubiquitin ligase activity on histone h2a.
98	nearly abolishes ubiquitin ligase activity on histone h2a.
168	decreases ubiquitin ligase activity on histone h2a.
247	reduced interaction with cbx7.
258	reduced interaction with cbx7.
262	reduced interaction with cbx7.

Function

Pathways and Gene Ontology

Reactome pathways

10 pathways

ID	Pathway
R-HSA-2559580	Oxidative Stress Induced Senescence
R-HSA-3108214	SUMOylation of DNA damage response and repair proteins
R-HSA-3899300	SUMOylation of transcription cofactors
R-HSA-4551638	SUMOylation of chromatin organization proteins
R-HSA-4570464	SUMOylation of RNA binding proteins
R-HSA-4655427	SUMOylation of DNA methylation proteins
R-HSA-8939243	RUNX1 interacts with co-factors whose precise effect on RUNX1 targets is not known
R-HSA-8943724	Regulation of PTEN gene transcription
R-HSA-8953750	Transcriptional Regulation by E2F6
R-HSA-9976102	Differentiation of naive CD4+ T cells to T helper 2 cells (Th2 cells)

MSigDB gene sets: 837 (showing top): GOBP_MYELOID_CELL_DIFFERENTIATION, BORCZUK_MALIGNANT_MESOTHELIOMA_UP, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, BENPORATH_ES_WITH_H3K27ME3, GOBP_AXIS_SPECIFICATION, GOBP_MYELOID_CELL_HOMEOSTASIS, GOBP_MYELOID_CELL_DEVELOPMENT, GOBP_INFLAMMATORY_RESPONSE, CMYB_01, GOBP_ERYTHROCYTE_HOMEOSTASIS, MAZ_Q6, GOBP_GROWTH, GOBP_PROTEIN_TARGETING, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, BROWNE_HCMV_INFECTION_16HR_UP

GO Biological Process (11): negative regulation of transcription by RNA polymerase II (GO:0000122), mitotic cell cycle (GO:0000278), gastrulation with mouth forming second (GO:0001702), chromatin remodeling (GO:0006338), germ cell development (GO:0007281), anterior/posterior axis specification (GO:0009948), gene expression (GO:0010467), protein ubiquitination (GO:0016567), epigenetic regulation of gene expression (GO:0040029), obsolete negative regulation of DNA-binding transcription factor activity (GO:0043433), chromatin organization (GO:0006325)

GO Molecular Function (9): chromatin binding (GO:0003682), zinc ion binding (GO:0008270), ubiquitin protein ligase activity (GO:0061630), RING-like zinc finger domain binding (GO:0071535), histone H2AK119 ubiquitin ligase activity (GO:0140862), ubiquitin-protein transferase activity (GO:0004842), protein binding (GO:0005515), transferase activity (GO:0016740), metal ion binding (GO:0046872)

GO Cellular Component (12): ubiquitin ligase complex (GO:0000151), euchromatin (GO:0000791), sex chromatin (GO:0001739), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), nuclear body (GO:0016604), PcG protein complex (GO:0031519), PRC1 complex (GO:0035102), MLL1 complex (GO:0071339), heterochromatin (GO:0000792), chromosome (GO:0005694)

Reactome top-level categories

Rollup of top-6 pathways:

Category	Pathways
SUMO E3 ligases SUMOylate target proteins	5
Cellular Senescence	1
Transcriptional regulation by RUNX1	1
PTEN Regulation	1
Generic Transcription Pathway	1
Differentiation of T cells	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
binding	2
chromatin	2
cellular anatomical structure	2
intracellular membraneless organelle	2
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
negative regulation of DNA-templated transcription	1
cell cycle	1
mitotic nuclear division	1
gastrulation	1
chromatin organization	1
developmental process involved in reproduction	1
gamete generation	1
cellular process involved in reproduction in multicellular organism	1
cell development	1
axis specification	1
anterior/posterior pattern specification	1
macromolecule biosynthetic process	1
protein modification by small protein conjugation	1
chromatin remodeling	1
regulation of gene expression	1
cellular component organization	1
transition metal ion binding	1
ubiquitin-protein transferase activity	1
ubiquitin-like protein ligase activity	1
protein domain specific binding	1
histone H2A ubiquitin ligase activity	1
ubiquitin-like protein transferase activity	1
catalytic activity	1
cation binding	1
intracellular protein-containing complex	1
transferase complex	1
heterochromatin	1
sex chromosome	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
intracellular anatomical structure	1
nucleoplasm	1
nuclear protein-containing complex	1
nuclear ubiquitin ligase complex	1

Protein interactions and networks

STRING

2093 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RNF2	BMI1	P35226	999
RNF2	PHC1	P78364	998
RNF2	PCGF1	Q9BSM1	997
RNF2	PCGF6	Q9BYE7	997
RNF2	RYBP	Q8N488	996
RNF2	CBX2	Q14781	995
RNF2	SUZ12	Q15022	995
RNF2	KDM2B	Q8NHM5	995
RNF2	R4GMX3	R4GMX3	993
RNF2	YAF2	Q8IY57	992
RNF2	PCGF2	P35227	991
RNF2	EZH2	Q15910	983
RNF2	RING1	Q06587	983
RNF2	CBX4	O00257	962
RNF2	EED	O75530	950

IntAct

385 interactions, top by confidence:

A	B	Type	Score
RNF2	RYBP	psi-mi:“MI:0915”(physical association)	0.970
RNF2	RYBP	psi-mi:“MI:0407”(direct interaction)	0.970
RYBP	RNF2	psi-mi:“MI:0915”(physical association)	0.970
RNF2	CBX7	psi-mi:“MI:0407”(direct interaction)	0.960
RNF2	CBX7	psi-mi:“MI:0915”(physical association)	0.960
RNF2	BMI1	psi-mi:“MI:0915”(physical association)	0.960
BMI1	RNF2	psi-mi:“MI:0915”(physical association)	0.960
PCGF2	RNF2	psi-mi:“MI:0915”(physical association)	0.950
RNF2	PCGF1	psi-mi:“MI:0915”(physical association)	0.950
BMI1	CBX7	psi-mi:“MI:0914”(association)	0.940
CBX7	BMI1	psi-mi:“MI:0914”(association)	0.940
RNF2	CBX8	psi-mi:“MI:0407”(direct interaction)	0.920
RYBP	CSNK2A2	psi-mi:“MI:0914”(association)	0.900
RNF2	PCGF5	psi-mi:“MI:0914”(association)	0.890
PCGF5	RNF2	psi-mi:“MI:0915”(physical association)	0.890
PCGF1	BCOR	psi-mi:“MI:0914”(association)	0.880

BioGRID (1336): RNF2 (Co-purification), RNF2 (Reconstituted Complex), HIST2H2AC (Biochemical Activity), HIST2H2AC (Biochemical Activity), UBE2D3 (Reconstituted Complex), BMI1 (Co-crystal Structure), HIST1H2AB (Biochemical Activity), UBE2D3 (Biochemical Activity), RNF2 (Protein-peptide), RNF2 (Affinity Capture-MS), RNF2 (Affinity Capture-MS), HIST4H4 (Affinity Capture-MS), NCL (Affinity Capture-MS), NUMA1 (Affinity Capture-MS), CBX8 (Affinity Capture-MS)

ESM2 similar proteins: A1CHL6, A1CX69, A2QIL5, A6RYB8, A7F0W2, A7KAL2, B8NLZ3, J4W0G2, O08678, O14019, O15297, O80492, P08018, P11792, P25333, P27448, P33294, P33886, P50530, Q02280, Q0CLX3, Q0KIA2, Q1DN93, Q2H6X2, Q2UGZ7, Q3ZDQ4, Q4KLY4, Q4WPF2, Q52EB3, Q5BCU8, Q5K2C1, Q5R9J5, Q61074, Q6C7U0, Q6FJ85, Q6H9I1, Q6YTI2, Q757X8, Q7K4Q5, Q7RX99

Diamond homologs: A1YER5, A1YFY1, A2T6X5, H2KYH3, O35730, O94264, Q06587, Q0WX00, Q4KLY4, Q5R9J5, Q5TJF3, Q66J69, Q6MGB6, Q7ZWM8, Q803I4, Q8WMN5, Q94AY3, Q99496, Q9CQJ4, Q9FKW0, Q9M9Y4, Q9VB08, P78317, Q9QZS2, A0JN74, G2Q0E2, K7N6K2, O19085, O35445, O54952, O70418, O74747, O77666, P10862, P14373, P15533, P18892, P19474, P48754, P62603

SIGNOR signaling

7 interactions.

A	Effect	B	Mechanism
BCOR	“up-regulates activity”	RNF2	binding
KDM2B	“up-regulates activity”	RNF2	binding
UBAP2L	“up-regulates activity”	RNF2	binding
RNF2	“form complex”	“Polycomb repressive complex 1”	binding
Ub:E2	“up-regulates activity”	RNF2	ubiquitination
RNF2	“down-regulates quantity by destabilization”	AMBRA1	ubiquitination
RNF2	“form complex”	“Noncanonical PRC1”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 119 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
SUMOylation of DNA methylation proteins	8	66.3×	1e-11
RUNX1 interacts with co-factors whose precise effect on RUNX1 targets is not known	15	55.6×	9e-21
Transcriptional Regulation by E2F6	10	36.1×	1e-11
Synthesis of active ubiquitin: roles of E1 and E2 enzymes	7	31.8×	8e-08
SUMOylation of transcription cofactors	9	27.0×	2e-09
Differentiation of naive CD4+ T cells to T helper 2 cells (Th2 cells)	13	23.5×	2e-12
SUMOylation of RNA binding proteins	8	23.5×	8e-08
Regulation of PTEN gene transcription	10	22.0×	2e-09

GO biological processes:

GO term	Partners	Fold	FDR
negative regulation of proteasomal ubiquitin-dependent protein catabolic process	6	23.8×	2e-05
protein K11-linked ubiquitination	6	23.3×	2e-05
protein monoubiquitination	5	17.0×	8e-04
protein K48-linked ubiquitination	9	15.0×	1e-06
protein K63-linked ubiquitination	5	13.2×	2e-03
chromatin remodeling	18	13.0×	9e-13
protein polyubiquitination	11	12.6×	2e-07
double-strand break repair	5	10.1×	6e-03

Disease & clinical

Cancer significance

From CIViC — curated cancer-variant interpretation:

BAP1 is a deubiquitylase thought to be a key regulator of many cancer-associated pathways. Germline alterations in BAP1 have been characterized as predisposing variants to familial melanocytic skin tumors. These alterations also have been linked to the development of mesothelioma, uveal melanoma, cutaneous melanoma and others. Clinically, the role of BAP1 is still being investigated. However, the development of intradermal tumors known as melanocytic BAP1-associated intradermal tumors (MBAITs) are enough for a patient to be subject to more intense surveillance to catch other malignancies as early as possible.

From intOGen — cancer-driver classification: loss-of-function (tumor-suppressor-like) across 14 cancer types — BRCA, CCRCC, CESC, CHOL, ESCA, HCC, PANCREAS, PLMESO, PRCC, RCC, SACA, SKCM…(+2 more).

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	32
Likely benign	2
Benign	1

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
1189036	NM_007212.4(RNF2):c.246T>G (p.Ser82Arg)	Pathogenic

SpliceAI

3916 predictions. Top by Δscore:

Variant	Effect	Δscore
1:185045646:GCCG:G	donor_gain	1.0000
1:185058508:TGG:T	donor_gain	1.0000
1:185058510:G:GT	donor_gain	1.0000
1:185058528:TAAA:T	donor_gain	1.0000
1:185058529:AAAA:A	donor_gain	1.0000
1:185058530:AAAA:A	donor_gain	1.0000
1:185087548:CCAG:C	acceptor_loss	1.0000
1:185087550:A:AG	acceptor_gain	1.0000
1:185087550:A:G	acceptor_loss	1.0000
1:185087551:G:GA	acceptor_gain	1.0000
1:185087551:GC:G	acceptor_gain	1.0000
1:185087551:GCA:G	acceptor_gain	1.0000
1:185087551:GCAA:G	acceptor_gain	1.0000
1:185087551:GCAAT:G	acceptor_gain	1.0000
1:185091736:G:GG	donor_gain	1.0000
1:185093056:TTTA:T	acceptor_loss	1.0000
1:185093058:TAGCA:T	acceptor_loss	1.0000
1:185093059:A:AG	acceptor_gain	1.0000
1:185093059:AGCAA:A	acceptor_loss	1.0000
1:185093060:G:A	acceptor_loss	1.0000
1:185093060:G:GG	acceptor_gain	1.0000
1:185093060:GC:G	acceptor_gain	1.0000
1:185093060:GCA:G	acceptor_gain	1.0000
1:185093060:GCAAC:G	acceptor_gain	1.0000
1:185093248:G:GT	donor_gain	1.0000
1:185093272:AACAG:A	donor_loss	1.0000
1:185093274:CAG:C	donor_loss	1.0000
1:185093275:AGG:A	donor_loss	1.0000
1:185093276:GG:G	donor_loss	1.0000
1:185093277:G:GA	donor_loss	1.0000

AlphaMissense

2241 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:185087602:T:A	W17R	1.000
1:185087602:T:C	W17R	1.000
1:185087609:T:A	L19H	1.000
1:185087620:G:A	E23K	1.000
1:185087621:A:T	E23V	1.000
1:185087630:G:C	R26P	1.000
1:185091610:T:A	V40D	1.000
1:185091625:T:A	L45Q	1.000
1:185091625:T:C	L45P	1.000
1:185091633:G:A	E48K	1.000
1:185091637:T:C	L49S	1.000
1:185091641:G:A	M50I	1.000
1:185091641:G:C	M50I	1.000
1:185091641:G:T	M50I	1.000
1:185091642:T:A	C51S	1.000
1:185091642:T:C	C51R	1.000
1:185091642:T:G	C51G	1.000
1:185091643:G:A	C51Y	1.000
1:185091643:G:C	C51S	1.000
1:185091643:G:T	C51F	1.000
1:185091644:C:G	C51W	1.000
1:185091645:C:A	P52T	1.000
1:185091645:C:T	P52S	1.000
1:185091646:C:A	P52Q	1.000
1:185091646:C:G	P52R	1.000
1:185091646:C:T	P52L	1.000
1:185091648:A:T	I53F	1.000
1:185091649:T:A	I53N	1.000
1:185091649:T:C	I53T	1.000
1:185091649:T:G	I53S	1.000

dbSNP variants (sampled 300 via entrez): RS1000092836 (1:185102313 G>C), RS1000106561 (1:185073339 T>A,C), RS1000152528 (1:185089970 G>A), RS1000284586 (1:185096793 C>G,T), RS1000356663 (1:185094394 G>A), RS1000424669 (1:185063278 T>C), RS1000551702 (1:185063825 C>A,G), RS1000562542 (1:185051740 T>G), RS1000616206 (1:185095493 A>C,G), RS1000625402 (1:185046759 T>C), RS1000654729 (1:185069269 A>G), RS1000688021 (1:185095690 TCTTC>T), RS1000724115 (1:185067993 G>A,C), RS1000742464 (1:185074609 A>G), RS1000777821 (1:185063500 C>T)

Disease associations

OMIM: gene MIM:608985 | disease phenotypes: MIM:619460

GenCC curated gene-disease

Disease	Classification	Inheritance
Luo-Schoch-Yamamoto syndrome	Strong	Autosomal dominant

Mondo (1): Luo-Schoch-Yamamoto syndrome (MONDO:0859171)

Orphanet (0):

HPO phenotypes

35 total (30 of 35 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000154	Wide mouth
HP:0000160	Narrow mouth
HP:0000316	Hypertelorism
HP:0000322	Short philtrum
HP:0000377	Abnormal pinna morphology
HP:0000403	Recurrent otitis media
HP:0000445	Wide nose
HP:0000463	Anteverted nares
HP:0000483	Astigmatism
HP:0000486	Strabismus
HP:0000490	Deeply set eye
HP:0000527	Long eyelashes
HP:0000577	Exotropia
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001347	Hyperreflexia
HP:0001508	Failure to thrive
HP:0001511	Intrauterine growth retardation
HP:0001537	Umbilical hernia
HP:0001562	Oligohydramnios
HP:0001566	Widely-spaced maxillary central incisors
HP:0001773	Short foot
HP:0002553	Highly arched eyebrow
HP:0005180	Tricuspid regurgitation
HP:0005280	Depressed nasal bridge
HP:0007651	Ectropion of lower eyelids
HP:0007874	Almond-shaped palpebral fissure
HP:0008872	Feeding difficulties in infancy
HP:0010864	Severe intellectual disability

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST001762_325	Obesity-related traits	2.000000e-06
GCST004264_27	Clopidogrel active metabolite levels	2.000000e-07
GCST004264_3	Clopidogrel active metabolite levels	7.000000e-13
GCST004862_171	Itch intensity from mosquito bite adjusted by bite size	2.000000e-06

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0005119	antioxidant measurement
EFO:0007966	clopidogrel metabolite measurement
EFO:0008377	mosquito bite reaction itch intensity measurement
EFO:0008378	mosquito bite reaction size measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6066032 (PROTEIN-PROTEIN INTERACTION)

Clinical evidence (CIViC)

Drug × variant × indication: 9 predictive associations from 10 curated evidence items; also 4 prognostic, 1 functional.

Variant	Therapy	Indication	Effect	Level	CIViC
BAP1 Mutation	Olaparib	Malignant Mesothelioma	Sensitivity/Response	CIViC B	EID11740 +1
BRCA1 Loss-of-function OR BAP1 Loss-of-function	Rucaparib	Malignant Mesothelioma	Sensitivity/Response	CIViC B	EID11739
BAP1 Mutation	Everolimus + Sunitinib	Renal Cell Carcinoma	Resistance	CIViC B	EID5339
BAP1 ALTERNATIVE TRANSCRIPT (ATI)	Olaparib + Apitolisib	Malignant Mesothelioma	Sensitivity/Response	CIViC D	EID5929
BAP1 Loss	Olaparib	Renal Carcinoma	Sensitivity/Response	CIViC D	EID5930
BAP1 Loss	EPZ011989	Malignant Pleural Mesothelioma	Sensitivity/Response	CIViC D	EID8329
BAP1 Mutation	CDK4/6 Inhibition	Malignant Pleural Mesothelioma	Sensitivity/Response	CIViC D	EID12008
BAP1 Mutation	Trichostatin A + Vorinostat + Panobinostat + Valproic Acid	Uveal Melanoma	Sensitivity/Response	CIViC D	EID1234
BAP1 Loss	Mocetinostat + Vorinostat	Malignant Mesothelioma	Sensitivity/Response	CIViC E	EID1235

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

CTD chemical–gene interactions

26 total (human), top 26 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	decreases methylation, decreases response to substance	2
aristolochic acid I	decreases expression	1
FR900359	increases phosphorylation	1
bisphenol A	decreases methylation	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
jinfukang	decreases expression	1
LDN 193189	affects cotreatment, increases expression	1
Bortezomib	increases expression	1
Acetaminophen	increases expression	1
Air Pollutants	increases abundance, decreases methylation	1
Caffeine	decreases phosphorylation	1
Calcitriol	increases expression	1
Diethylstilbestrol	increases expression	1
Doxorubicin	decreases expression	1
Fonofos	decreases methylation	1
Enzyme Inhibitors	decreases activity, increases O-linked glycosylation	1
Gold	decreases expression	1
Ivermectin	decreases expression	1
Nitrogen Dioxide	decreases methylation, increases abundance	1
Parathion	decreases methylation	1
Phenobarbital	affects expression	1
Valproic Acid	decreases methylation	1
Cyclosporine	increases expression	1
Lactic Acid	decreases expression	1

ChEMBL screening assays

16 unique, capped per target: 16 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5548040	Binding	PROTAC activity at CRBN/RING1B in human K562 cells assessed as degradation of RING1B protein expression incubated for 24 hrs by Western blotting analysis	Discovery and Characterization of a Novel Cereblon-Recruiting PRC1 Bridged PROTAC Degrader. — J Med Chem

Cellosaurus cell lines

16 cell lines: 11 cancer cell line, 5 embryonic stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_A5W5	SEES3-1V human RNF2, clone1	Embryonic stem cell	Male
CVCL_A5W6	SEES3-1V human RNF2, clone2	Embryonic stem cell	Male
CVCL_A5W7	SEES3-1V human RNF2, clone3	Embryonic stem cell	Male
CVCL_B2DY	Abcam HeLa RNF2 KO	Cancer cell line	Female
CVCL_B8NV	Abcam HCT 116 RNF2 KO	Cancer cell line	Male
CVCL_B9B7	Abcam MCF-7 RNF2 KO	Cancer cell line	Female
CVCL_B9R6	Abcam A-549 RNF2 KO	Cancer cell line	Male
CVCL_DX52	HAP1 RING1 (-) RNF2 (-) 1	Cancer cell line	Male
CVCL_E1NP	HAP1 RING1 (-) RNF2 (-) 2	Cancer cell line	Male
CVCL_TJ30	HAP1 RNF2 (-) 1	Cancer cell line	Male

Clinical trials (associated diseases)

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