UHRF2

Summary

UHRF2 (ubiquitin like with PHD and ring finger domains 2, HGNC:12557) is a protein-coding gene on chromosome 9p24.1, encoding E3 ubiquitin-protein ligase UHRF2 (Q96PU4). E3 ubiquitin ligase that plays important roles in DNA methylation, histone modifications, cell cycle and DNA repair.

This gene encodes a nuclear protein which is involved in cell-cycle regulation. The encoded protein is a ubiquitin-ligase capable of ubiquinating PCNP (PEST-containing nuclear protein), and together they may play a role in tumorigenesis. The encoded protein contains an NIRF_N domain, a PHD finger, a set- and ring-associated (SRA) domain, and a RING finger domain and several of these domains have been shown to be essential for the regulation of cell proliferation. This protein may also have a role in intranuclear degradation of polyglutamine aggregates. Alternative splicing results in multiple transcript variants some of which are non-protein coding.

Source: NCBI Gene 115426 — RefSeq curated summary.

At a glance

• GWAS associations: 11
• Clinical variants (ClinVar): 84 total — 1 pathogenic
• MANE Select transcript: NM_152896

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:12557
Approved symbol	UHRF2
Name	ubiquitin like with PHD and ring finger domains 2
Location	9p24.1
Locus type	gene with protein product
Status	Approved
Aliases	RNF107, NIRF, URF2, MGC33463, TDRD23
Ensembl gene	ENSG00000147854
Ensembl biotype	protein_coding
OMIM	615211
Entrez	115426

Gene structure

Transcript identifiers

Ensembl transcripts: 18 — 8 protein_coding_CDS_not_defined, 6 protein_coding, 3 nonsense_mediated_decay, 1 retained_intron

ENST00000276893, ENST00000381373, ENST00000450508, ENST00000461236, ENST00000468435, ENST00000469298, ENST00000477183, ENST00000479000, ENST00000481049, ENST00000481243, ENST00000484159, ENST00000485617, ENST00000492853, ENST00000850598, ENST00000875266, ENST00000875267, ENST00000875268, ENST00000934278

RefSeq mRNA: 1 — MANE Select: NM_152896 NM_152896

CCDS: CCDS6469

Canonical transcript exons

ENST00000276893 — 16 exons

Exon	Start	End
ENSE00001885825	6413199	6413643
ENSE00003460175	6500552	6500709
ENSE00003496734	6420912	6421142
ENSE00003501116	6506033	6507054
ENSE00003516753	6481643	6481766
ENSE00003542653	6504593	6504691
ENSE00003550152	6498018	6498158
ENSE00003568369	6497198	6497360
ENSE00003600319	6477622	6477808
ENSE00003610058	6499835	6499931
ENSE00003620888	6493826	6493932
ENSE00003633686	6481992	6482099
ENSE00003644061	6460573	6460791
ENSE00003686544	6433914	6434173
ENSE00003694501	6475391	6475500
ENSE00003694615	6486821	6486925

Expression profiles

Bgee: expression breadth ubiquitous, 261 present calls, max score 99.65.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 33.5573 / max 568.3563, expressed in 1818 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
95990	19.3311	1805
95991	8.1311	1724
95989	2.8868	1422
95988	1.0222	664
95994	0.9684	447
95993	0.5900	278
95992	0.4106	177
205423	0.2172	55

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
secondary oocyte	CL:0000655	99.65	gold quality
oocyte	CL:0000023	99.03	gold quality
epithelial cell of pancreas	CL:0000083	98.04	gold quality
calcaneal tendon	UBERON:0003701	97.51	gold quality
tibia	UBERON:0000979	97.41	gold quality
thymus	UBERON:0002370	96.60	gold quality
sperm	CL:0000019	96.11	gold quality
ventricular zone	UBERON:0003053	95.97	gold quality
germinal epithelium of ovary	UBERON:0001304	95.63	gold quality
bone marrow	UBERON:0002371	95.49	gold quality
bone marrow cell	CL:0002092	95.34	gold quality
upper arm skin	UBERON:0004263	95.14	gold quality
superficial temporal artery	UBERON:0001614	95.11	gold quality
lymph node	UBERON:0000029	94.65	gold quality
visceral pleura	UBERON:0002401	94.32	gold quality
cartilage tissue	UBERON:0002418	94.25	gold quality
oviduct epithelium	UBERON:0004804	94.17	gold quality
parietal pleura	UBERON:0002400	94.13	gold quality
trabecular bone tissue	UBERON:0002483	94.09	gold quality
ganglionic eminence	UBERON:0004023	94.00	gold quality
embryo	UBERON:0000922	93.99	gold quality
ileal mucosa	UBERON:0000331	93.91	gold quality
tonsil	UBERON:0002372	93.87	gold quality
corpus callosum	UBERON:0002336	93.84	gold quality
palpebral conjunctiva	UBERON:0001812	93.80	gold quality
tibialis anterior	UBERON:0001385	93.66	gold quality
pylorus	UBERON:0001166	93.38	gold quality
adrenal tissue	UBERON:0018303	93.23	gold quality
skin of hip	UBERON:0001554	93.17	gold quality
epithelium of nasopharynx	UBERON:0001951	93.11	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.53

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 34)

• NIRF is involved in cell-cycle regulation (PMID:12176013)
• NIRF has ubiquitination activity, the hallmark of a ubiquitin ligase. PCNP was readily ubiquitinated in 293 and COS-7 cells, and NIRF ubiquitinated PCNP in vitro as well as in vivo. (PMID:14741369)
• NIRF is a ubiquitin ligase that is capable of ubiquitinating PCNP (PEST-containing nuclear protein). (PMID:14741369)
• Overexpression of NIRF induces cell cycle arrest at G1 phase. NIRF binds to the cyclin E-Cdk2 complex in vivo, and is phosphorylated by Cdk2 in vitro. (PMID:15178429)
• may participate in the G1/S transition regulation (PMID:15178429)
• UHRF-2 is an essential molecule for nuclear pQ degradation as a component of nuclear PQC machinery in mammalian cells (PMID:19218238)
• Growth-inhibitory effect of let-7a on the A549 cells in vitro and in vivo may be explained in part by le-7a-induced suppression of NIRF and elevation of p21(WAF1). (PMID:19818775)
• the cooperative interplay of Uhrf2 domains may contribute to a tighter epigenetic control of gene expression in differentiated cells (PMID:21598301)
• NIRF is immediately adjacent to the single nucleotide polymorphism rs719725, which is reportedly associated with the risk of colorectal cancer. (PMID:21952639)
• NIRF is frequently upregulated in colorectal cancer and its oncogenicity can be suppressed by let-7a microRNA. (PMID:22018986)
• In the present study, ubiquitin ligase, NIRF, binds to hepatitis B virus core protein and leads to the proteasome-mediated degradation of hepatitis B virus core protein in vivo. (PMID:22072112)
• NIRF may contribute to the coupling between the cell cycle network and the epigenetic landscape (PMID:22673569)
• Low UHRF2 mRNA expression is associated with malignant glioma. (PMID:23244124)
• UHRF2, a ubiquitin E3 ligase, acts as a small ubiquitin-like modifier E3 ligase for zinc finger protein 131 (PMID:23404503)
• UHRF2, the homolog of UHRF1, interacts with N-methylpurine DNA glycosylase (MPG) in cancer cells. (PMID:23537643)
• UHRF2 is a transcriptional target of E2F, that it directly interacts with E2F1. (PMID:23833190)
• UHRF2 may contribute to the progression of colon carcinogenesis and function as a novel prognostic indicator after curative operation (PMID:24573556)
• A hydrogen bond between the hydroxyl group of 5hmC and UHRF2-SRA is critical for their preferential binding. (PMID:24813944)
• Results show that UHRF2 down-regulates a number of epithelial-mesenchymal transition markers and up-regulates the expression of transcription factors. The study also suggests that UHRF2 play a role in tumor metastasis. (PMID:27114453)
• study suggests that ZNF618 is a key protein that regulates UHRF2 function as a specific 5hmC reader in vivo. (PMID:27129234)
• UHRF2 expression is reduced in some leukemia cell lines, this correlates with promoter hypermethylation, and similar UHRF2 methylation profiles are seen in primary human leukemia samples. Thus, UHRF2 and 5hmC are widely present in differentiated human tissues, and UHRF2 protein is poorly expressed or mislocalized in diverse human cancers. (PMID:27738314)
• TIP60 acted downstream of UHRF2 to regulate H3K9ac and H3K14ac expression. (PMID:27743347)
• The overexpression of UHRF2 increased the expression of H3K9ac in L02 normal cells (P<0.01), but decreased the expression of histone H3 lysine 9 acetylation in HepG2 cancer cells. (PMID:28004105)
• Here, we report the complex structure of PCNA and the peptide ((784)NEILQTLLDLFFPGYSK(800)) derived from UHRF2 that contains a PIP box. Structural analysis combined with mutagenesis experiments provide the molecular basis for the recognition of UHRF2 by PCNA via PIP-box. (PMID:28951215)
• Uncoupling of UHRF2 from the DNA methylation maintenance program is linked to differences in the molecular readout of chromatin signatures that connect UHRF1 to ubiquitination of histone H3. (PMID:29506131)
• UHRF2 may be a negative regulator of EMT and a novel prognostic biomarker for ESCC. (PMID:29909415)
• Immunoprecipitation and immunofluorescence staining reveled that UHRF2 combined with p21 in the nucleus. In addition, UHRF2 degraded p21 through ubiquitination and shortened the half-life of p21. (PMID:29923055)
• UHRF2 promotes intestinal tumorigenesis through stabilization of TCF4 mediated Wnt/beta-catenin signaling. (PMID:32372448)
• UV-induced activation of ATR is mediated by UHRF2. (PMID:33848395)
• HBx promotes hepatocarcinogenesis by enhancing phosphorylation and blocking ubiquitinylation of UHRF2. (PMID:33876395)
• UHRF2 commissions the completion of DNA demethylation through allosteric activation by 5hmC and K33-linked ubiquitination of XRCC1. (PMID:34111398)
• IGF2BP1/UHRF2 Axis Mediated by miR-98-5p to Promote the Proliferation of and Inhibit the Apoptosis of Esophageal Squamous Cell Carcinoma. (PMID:34162562)
• UHRF2 promotes Hepatocellular Carcinoma Progression by Upregulating ErbB3/Ras/Raf Signaling Pathway. (PMID:34400880)
• MiR-196a promotes the proliferation and migration of esophageal cancer via the UHRF2/TET2 axis. (PMID:34826027)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Uhrf2	ENSMUSG00000024817
rattus_norvegicus	Uhrf2	ENSRNOG00000011308

Paralogs (2): SHISA5 (ENSG00000164054), UHRF1 (ENSG00000276043)

Protein

Protein identifiers

E3 ubiquitin-protein ligase UHRF2 — Q96PU4 (reviewed: Q96PU4)

Alternative names: Np95/ICBP90-like RING finger protein, Nuclear protein 97, Nuclear zinc finger protein Np97, RING finger protein 107, RING-type E3 ubiquitin transferase UHRF2, Ubiquitin-like PHD and RING finger domain-containing protein 2, Ubiquitin-like-containing PHD and RING finger domains protein 2

All UniProt accessions (3): Q96PU4, A0A0A0MSQ3, B1AL33

UniProt curated annotations — full annotation on UniProt →

Function. E3 ubiquitin ligase that plays important roles in DNA methylation, histone modifications, cell cycle and DNA repair. Acts as a specific reader for 5-hydroxymethylcytosine (5hmC) and thereby recruits various substrates to these sites to ubiquitinate them. This activity also allows the maintenance of 5mC levels at specific genomic loci and regulates neuron-related gene expression. Participates in cell cycle regulation by ubiquitinating cyclins CCND1 and CCNE1 and thereby inducing G1 arrest. Also ubiquitinates PCNP leading to its degradation by the proteasome. Plays an active role in DNA damage repair by ubiquitinating p21/CDKN1A leading to its proteasomal degradation. Also promotes DNA repair by acting as an interstrand cross-links (ICLs) sensor. Mechanistically, cooperates with UHRF1 to ensure recruitment of FANCD2 to ICLs, leading to FANCD2 monoubiquitination and subsequent activation. Contributes to UV-induced DNA damage response by physically interacting with ATR in response to irradiation, thereby promoting ATR activation.

Subunit / interactions. Homodimer; disulfide-linked. Binds methylated CpG containing oligonucleotides. Interacts with H3; the interaction has a preference for the ‘Lys-9’ trimethylated form of H3 (H3K9me3). Interacts with PCNP. Interacts with HDAC1. Interacts directly with CCNE1; the interaction ubiquitinates CCNE1 and appears independent of CCNE1 phosphorylation. Interacts with CCND1; the interaction ubiquitinates CCND1 and appears independent of CCND1 phosphorylation. Interacts with p53/TP53 and RB1. Interacts with UBE2I. Interacts with ZNF618. Interacts with UHRF1. Interacts with FANCD2. Interacts with ATR. Interacts with PCNA.

Subcellular location. Nucleus. Chromosome.

Post-translational modifications. May be autoubiquitinated; which may lead to proteasomal degradation. Phosphorylated. Phosphorylation may be mediated by CDK2. Autosumoylated.

Disease relevance. Associated with various cancers. DNA copy number loss is found in multiple kinds of malignancies originating from the brain, breast, stomach, kidney, hematopoietic tissue and lung.

Activity regulation. E3 ligase activity is robustly activated by 5-hydroxymethylcytosine.

Domain organisation. The YDG domain recognizes and binds 5-hydroxymethylcytosine (5hmC).

Induction. Up-regulated in proliferating fetal lung fibroblasts and in U-937 myeloid leukemia cells. Down-regulated in these cells by growth arrest and differentiation. In other cell types which cannot leave the cell cycle, such as tumoral HT-1080 and Hep-G2, levels are consistently up-regulated.

Pathway. Protein modification; protein ubiquitination.

Isoforms (2)

UniProt ID	Names	Canonical?
Q96PU4-1	1	yes
Q96PU4-2	2, a

RefSeq proteins (1): NP_690856* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000626	Ubiquitin-like_dom	Domain
IPR001841	Znf_RING	Domain
IPR001965	Znf_PHD	Domain
IPR003105	SRA_YDG	Domain
IPR011011	Znf_FYVE_PHD	Homologous_superfamily
IPR013083	Znf_RING/FYVE/PHD	Homologous_superfamily
IPR015947	PUA-like_sf	Homologous_superfamily
IPR017907	Znf_RING_CS	Conserved_site
IPR019787	Znf_PHD-finger	Domain
IPR021991	TTD_dom	Domain
IPR029071	Ubiquitin-like_domsf	Homologous_superfamily
IPR036987	SRA-YDG_sf	Homologous_superfamily
IPR045134	UHRF1/2-like	Family
IPR047407	Tudor_UHRF2_rpt1	Domain
IPR047466	RING-HC_UHRF2	Domain
IPR047467	PHD_UHRF2	Domain
IPR047468	Ubl_UHRF2	Domain

Pfam: PF00240, PF00628, PF02182, PF12148

UniProt features (88 total): strand 32, helix 17, turn 14, region of interest 6, compositionally biased region 3, mutagenesis site 3, sequence conflict 3, domain 2, splice variant 2, zinc finger region 2, chain 1, modified residue 1, disulfide bond 1, sequence variant 1

Structure

Experimental structures (PDB)

9 structures.

PDB	Method	Resolution (Å)
4PW7	X-RAY DIFFRACTION	2
1Z6U	X-RAY DIFFRACTION	2.1
5YCO	X-RAY DIFFRACTION	2.2
4PW5	X-RAY DIFFRACTION	2.2
4TVR	X-RAY DIFFRACTION	2.29
3OLN	X-RAY DIFFRACTION	2.3
4PW6	X-RAY DIFFRACTION	3.79
1WY8	SOLUTION NMR
2E6S	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96PU4-F1	80.81	0.55

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 (1): 667

Disulfide bonds (1): 704

Mutagenesis-validated functional residues (3):

Position	Phenotype
307	no effect on autosumoylation.
548	no effect on autosumoylation.
735	no effect on autosumoylation, nor on znf131 sumoylation.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-3899300	SUMOylation of transcription cofactors

MSigDB gene sets: 165 (showing top): ACTACCT_MIR196A_MIR196B, FREAC2_01, HNF3ALPHA_Q6, RORA1_01, TGACCTY_ERR1_Q2, GOBP_NEGATIVE_REGULATION_OF_GENE_EXPRESSION_EPIGENETIC, GOBP_PEPTIDYL_LYSINE_MODIFICATION, SNIJDERS_AMPLIFIED_IN_HEAD_AND_NECK_TUMORS, GOBP_REGULATION_OF_CELL_CYCLE, GOBP_PROTEIN_AUTOUBIQUITINATION, GOBP_PROTEIN_SUMOYLATION, AAAGGGA_MIR204_MIR211, GOBP_POST_TRANSLATIONAL_PROTEIN_MODIFICATION, TTGGAGA_MIR5155P_MIR519E, TAATGTG_MIR323

GO Biological Process (7): regulation of transcription by RNA polymerase II (GO:0006357), protein ubiquitination (GO:0016567), protein sumoylation (GO:0016925), cell differentiation (GO:0030154), negative regulation of gene expression via chromosomal CpG island methylation (GO:0044027), regulation of cell cycle (GO:0051726), protein autoubiquitination (GO:0051865)

GO Molecular Function (11): DNA binding (GO:0003677), ubiquitin-protein transferase activity (GO:0004842), zinc ion binding (GO:0008270), SUMO transferase activity (GO:0019789), histone binding (GO:0042393), RNA polymerase II-specific DNA-binding transcription factor binding (GO:0061629), ubiquitin protein ligase activity (GO:0061630), histone H3K9me2/3 reader activity (GO:0062072), protein binding (GO:0005515), transferase activity (GO:0016740), metal ion binding (GO:0046872)

GO Cellular Component (5): heterochromatin (GO:0000792), nucleus (GO:0005634), nucleoplasm (GO:0005654), pericentric heterochromatin (GO:0005721), chromosome (GO:0005694)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
SUMO E3 ligases SUMOylate target proteins	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein modification by small protein conjugation	2
ubiquitin-like protein transferase activity	2
regulation of DNA-templated transcription	1
transcription by RNA polymerase II	1
peptidyl-lysine modification	1
cellular developmental process	1
negative regulation of gene expression, epigenetic	1
cell cycle	1
regulation of cellular process	1
protein ubiquitination	1
nucleic acid binding	1
transition metal ion binding	1
protein binding	1
DNA-binding transcription factor binding	1
ubiquitin-protein transferase activity	1
ubiquitin-like protein ligase activity	1
histone H3 reader activity	1
binding	1
catalytic activity	1
cation binding	1
chromatin	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
cellular anatomical structure	1
chromosome, centromeric region	1
heterochromatin	1
intracellular membraneless organelle	1

Protein interactions and networks

STRING

1316 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
UHRF2	HDAC1	Q13547	805
UHRF2	DNMT1	P26358	774
UHRF2	PCNP	Q8WW12	734
UHRF2	TP53	P04637	679
UHRF2	TET2	Q6N021	664
UHRF2	ZBTB38	Q8NAP3	663
UHRF2	DNMT3A	Q9Y6K1	657
UHRF2	ZBTB4	Q9P1Z0	647
UHRF2	DNMT3B	Q9UBC3	644
UHRF2	RB1	P06400	639
UHRF2	ZBTB33	Q86T24	614
UHRF2	MBD4	O95243	603
UHRF2	MECP2	P51608	598
UHRF2	TDG	Q13569	557
UHRF2	TET3	O43151	539

IntAct

62 interactions, top by confidence:

A	B	Type	Score
CCND1		psi-mi:“MI:0220”(ubiquitination reaction)	0.740
CDK2	UHRF2	psi-mi:“MI:0915”(physical association)	0.730
UHRF2	CDK2	psi-mi:“MI:0915”(physical association)	0.730
UHRF2	CDK2	psi-mi:“MI:0407”(direct interaction)	0.730
UHRF2	CCND1	psi-mi:“MI:0915”(physical association)	0.600
CCNE1	UHRF2	psi-mi:“MI:0915”(physical association)	0.600
UHRF2	CCNE1	psi-mi:“MI:0915”(physical association)	0.600
UHRF2	RB1	psi-mi:“MI:0915”(physical association)	0.590
HMGB1	UHRF2	psi-mi:“MI:0915”(physical association)	0.550
TP53	UHRF2	psi-mi:“MI:0915”(physical association)	0.520
CCNE1		psi-mi:“MI:0220”(ubiquitination reaction)	0.440
UHRF2	ACTA2	psi-mi:“MI:0915”(physical association)	0.400
UHRF2	CDK1	psi-mi:“MI:0915”(physical association)	0.400
CDK4	UHRF2	psi-mi:“MI:0915”(physical association)	0.400
UHRF2	CDK6	psi-mi:“MI:0915”(physical association)	0.400
UHRF2	PCNA	psi-mi:“MI:0915”(physical association)	0.400
MCL1	UHRF2	psi-mi:“MI:0915”(physical association)	0.400
UHRF2	BCL2L1	psi-mi:“MI:0915”(physical association)	0.400
BAX	UHRF2	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (213): UHRF2 (Biochemical Activity), UHRF2 (Synthetic Lethality), UHRF2 (Affinity Capture-MS), ZNF618 (Affinity Capture-MS), PARP1 (Affinity Capture-MS), HSPA1L (Affinity Capture-MS), XRCC5 (Affinity Capture-MS), USP7 (Affinity Capture-MS), XRCC6 (Affinity Capture-MS), UHRF2 (Affinity Capture-Western), ZNF618 (Affinity Capture-Western), UHRF2 (Reconstituted Complex), ZNF618 (Reconstituted Complex), UHRF2 (Co-localization), KAT5 (Affinity Capture-Western)

ESM2 similar proteins: A0A024RBG1, A2VE79, A3KMI0, A7E320, B0R160, B6CHA3, F4JLK2, F6UA42, O22951, O45830, O59761, O95989, P0C027, P0C028, P32271, Q08C92, Q09790, Q566C7, Q58CW0, Q5RAF0, Q5RDX4, Q5U243, Q6NPD7, Q6P5D3, Q7TMI3, Q7TPK1, Q7YTB0, Q8BJM7, Q8CIG3, Q8L7W2, Q8NB78, Q8NFP7, Q8R2U6, Q8VDF2, Q8VHT6, Q91WU5, Q96G61, Q96PU4, Q96T88, Q99321

Diamond homologs: A0A286Y9D1, A1YVX4, A7E320, B2KF05, B2RRD7, B6CHA3, F4KBP5, F6UA42, G5E8P1, G5EBZ4, O54826, O75164, O94880, O94953, P0CB22, P29375, P34447, P41229, P41230, P47156, P55197, P55198, P55201, Q0P4S5, Q12311, Q20318, Q22516, Q29EQ3, Q30DN6, Q38JA7, Q3UXZ9, Q5E9T7, Q5RD88, Q5TKR9, Q62240, Q6GQJ2, Q6IE81, Q6IE82, Q6IQX0, Q6K431

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
Ub:E2	“up-regulates activity”	UHRF2	ubiquitination
UHRF2	“down-regulates quantity by destabilization”	PCNP	polyubiquitination
UHRF2	“down-regulates quantity by destabilization”	CCND1	ubiquitination
UHRF2	“down-regulates quantity by destabilization”	CCNE1	ubiquitination

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 44 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
Defective binding of RB1 mutants to E2F1,(E2F2, E2F3)	6	92.8×	3e-09
TP53 Regulates Transcription of Cell Cycle Genes	6	79.6×	7e-09
TP53 Regulates Transcription of Genes Involved in G2 Cell Cycle Arrest	5	73.3×	3e-07
Regulation of MITF-M-dependent genes involved in cell cycle and proliferation	5	69.6×	3e-07
G1 Phase	7	67.2×	1e-09
Signaling by PTK6	5	66.3×	3e-07
Signaling by Non-Receptor Tyrosine Kinases	5	66.3×	3e-07
G0 and Early G1	5	53.6×	1e-06

GO biological processes:

GO term	Partners	Fold	FDR
G1/S transition of mitotic cell cycle	9	42.0×	6e-10
T cell receptor signaling pathway	5	17.6×	5e-04
protein polyubiquitination	6	16.1×	2e-04
chromatin remodeling	8	13.6×	3e-05
response to xenobiotic stimulus	8	12.8×	3e-05
negative regulation of gene expression	8	12.8×	3e-05
regulation of cell cycle	7	12.1×	1e-04
cell division	10	10.7×	7e-06

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	58
Likely benign	4
Benign	0

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
815187	GRCh37/hg19 9p24.3-23(chr9:203861-10666419)x1	Pathogenic

SpliceAI

3047 predictions. Top by Δscore:

Variant	Effect	Δscore
9:6413640:GCAG:G	donor_gain	1.0000
9:6413641:CAGG:C	donor_loss	1.0000
9:6413642:AGGT:A	donor_loss	1.0000
9:6413643:GGTGA:G	donor_loss	1.0000
9:6413644:G:A	donor_loss	1.0000
9:6420906:TTCTA:T	acceptor_loss	1.0000
9:6420907:TCTA:T	acceptor_loss	1.0000
9:6420908:CTAG:C	acceptor_loss	1.0000
9:6420909:TAGTT:T	acceptor_loss	1.0000
9:6420910:A:AG	acceptor_gain	1.0000
9:6420910:AGTT:A	acceptor_gain	1.0000
9:6420910:AGTTG:A	acceptor_gain	1.0000
9:6420911:G:GA	acceptor_gain	1.0000
9:6420911:GT:G	acceptor_gain	1.0000
9:6420911:GTT:G	acceptor_gain	1.0000
9:6420911:GTTG:G	acceptor_gain	1.0000
9:6420911:GTTGG:G	acceptor_gain	1.0000
9:6421140:AAGGT:A	donor_loss	1.0000
9:6421141:AGGTA:A	donor_loss	1.0000
9:6421142:GGTA:G	donor_loss	1.0000
9:6421143:G:GG	donor_gain	1.0000
9:6421143:GTAT:G	donor_loss	1.0000
9:6421144:T:A	donor_loss	1.0000
9:6433908:TTTTA:T	acceptor_loss	1.0000
9:6433909:TTTAG:T	acceptor_loss	1.0000
9:6433910:TTA:T	acceptor_loss	1.0000
9:6433911:TAGGT:T	acceptor_loss	1.0000
9:6433912:AGGTA:A	acceptor_loss	1.0000
9:6434169:GATGA:G	donor_gain	1.0000
9:6434170:A:G	donor_gain	1.0000

AlphaMissense

5252 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
9:6477732:T:A	C362S	1.000
9:6477732:T:C	C362R	1.000
9:6477733:G:A	C362Y	1.000
9:6477733:G:C	C362S	1.000
9:6477734:T:G	C362W	1.000
9:6481647:T:C	C389R	1.000
9:6481656:T:A	C392S	1.000
9:6481657:G:C	C392S	1.000
9:6481758:T:A	W426R	1.000
9:6481758:T:C	W426R	1.000
9:6481760:G:C	W426C	1.000
9:6481760:G:T	W426C	1.000
9:6482032:T:A	V442D	1.000
9:6482071:T:A	V455D	1.000
9:6482074:G:A	G456E	1.000
9:6482082:T:A	W459R	1.000
9:6482082:T:C	W459R	1.000
9:6482088:T:C	F461L	1.000
9:6482090:T:A	F461L	1.000
9:6482090:T:G	F461L	1.000
9:6482092:G:C	R462T	1.000
9:6486834:G:A	G469D	1.000
9:6486837:T:A	V470D	1.000
9:6486852:T:A	V475D	1.000
9:6486866:G:C	G480R	1.000
9:6486867:G:A	G480D	1.000
9:6486867:G:T	G480V	1.000
9:6486890:T:C	S488P	1.000
9:6486891:C:A	S488Y	1.000
9:6486891:C:T	S488F	1.000

dbSNP variants (sampled 300 via entrez): RS1000030437 (9:6501740 G>A,T), RS1000071316 (9:6443655 A>T), RS1000092506 (9:6438849 A>T), RS1000106101 (9:6466864 A>C,G), RS1000108952 (9:6496492 G>T), RS1000124740 (9:6462770 A>C), RS1000149281 (9:6428769 G>A), RS1000178225 (9:6495293 G>A,C), RS1000185426 (9:6415281 C>T), RS1000206891 (9:6446629 A>G), RS1000217461 (9:6427724 A>G), RS1000225075 (9:6500841 A>C,G), RS1000242114 (9:6495548 CCTT>C), RS1000264056 (9:6434387 C>T), RS1000301171 (9:6411440 T>C)

Disease associations

OMIM: gene MIM:615211 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

11 associations (top):

Study	Trait	p-value
GCST001588_15	Periodontal microbiota	3.000000e-06
GCST007563_22	Allergic disease (asthma, hay fever or eczema)	2.000000e-08
GCST007564_17	Asthma or allergic disease (pleiotropy)	2.000000e-10
GCST007564_32	Asthma or allergic disease (pleiotropy)	4.000000e-22
GCST008916_26	Asthma	3.000000e-64
GCST008916_47	Asthma	2.000000e-08
GCST008916_5	Asthma	7.000000e-17
GCST008916_83	Asthma	1.000000e-08
GCST008916_9	Asthma	4.000000e-18
GCST009798_28	Asthma	4.000000e-18
GCST009798_8	Asthma	5.000000e-67

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	decreases expression, increases expression, increases methylation	3
bisphenol A	affects cotreatment, decreases methylation, decreases expression	2
Dexamethasone	affects cotreatment, increases expression, decreases expression	2
Cyclosporine	increases expression	2
Cadmium Chloride	decreases expression	2
aristolochic acid I	decreases expression	1
GSK-J4	increases expression	1
FR900359	affects phosphorylation	1
bisphenol F	decreases expression, affects cotreatment	1
sotorasib	affects cotreatment, decreases expression	1
triphenyl phosphate	affects expression	1
arsenite	affects binding, decreases reaction	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
butyraldehyde	decreases expression	1
ferrous chloride	increases expression	1
beta-glycerophosphoric acid	affects cotreatment, increases expression	1
di-n-butylphosphoric acid	affects expression	1
pentabromodiphenyl ether	increases expression	1
2-palmitoylglycerol	increases expression	1
abrine	increases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	increases expression	1
trametinib	affects cotreatment, decreases expression	1
NVP-BKM120	affects cotreatment, decreases expression	1
Resveratrol	affects cotreatment, increases expression	1
Fulvestrant	affects cotreatment, decreases methylation	1
Leflunomide	increases expression	1
Air Pollutants	decreases expression, increases abundance	1
Ascorbic Acid	affects cotreatment, increases expression	1
Caffeine	decreases phosphorylation	1
Estradiol	affects expression	1

Clinical trials (associated diseases)

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