UHRF1

Summary

UHRF1 (ubiquitin like with PHD and ring finger domains 1, HGNC:12556) is a protein-coding gene on chromosome 19p13.3, encoding E3 ubiquitin-protein ligase UHRF1 (Q96T88). E3 ubiquitin-protein ligase that acts as a key epigenetic regulator by bridging DNA methylation and chromatin modification. It is a selective cancer dependency (DepMap: 35.1% of cell lines).

This gene encodes a member of a subfamily of RING-finger type E3 ubiquitin ligases. The protein binds to specific DNA sequences, and recruits a histone deacetylase to regulate gene expression. Its expression peaks at late G1 phase and continues during G2 and M phases of the cell cycle. It plays a major role in the G1/S transition by regulating topoisomerase IIalpha and retinoblastoma gene expression, and functions in the p53-dependent DNA damage checkpoint. It is regarded as a hub protein for the integration of epigenetic information. This gene is up-regulated in various cancers, and it is therefore considered to be a therapeutic target. Multiple transcript variants encoding different isoforms have been found for this gene. A related pseudogene exists on chromosome 12.

Source: NCBI Gene 29128 — RefSeq curated summary.

At a glance

• Gene–disease (curated): DNA repair disease (Moderate, GenCC) — +1 more curated relationship
• GWAS associations: 12
• Clinical variants (ClinVar): 73 total
• Phenotypes (HPO): 23
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 35.1% of screened cell lines
• MANE Select transcript: NM_001048201

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:12556
Approved symbol	UHRF1
Name	ubiquitin like with PHD and ring finger domains 1
Location	19p13.3
Locus type	gene with protein product
Status	Approved
Aliases	ICBP90, Np95, FLJ21925, RNF106, TDRD22
Ensembl gene	ENSG00000276043
Ensembl biotype	protein_coding
OMIM	607990
Entrez	29128

Gene structure

Transcript identifiers

Ensembl transcripts: 12 — 12 protein_coding

ENST00000612630, ENST00000613817, ENST00000615884, ENST00000616255, ENST00000620565, ENST00000622802, ENST00000624301, ENST00000650932, ENST00000932712, ENST00000932713, ENST00000932714, ENST00000953728

RefSeq mRNA: 5 — MANE Select: NM_001048201 NM_001048201, NM_001290050, NM_001290051, NM_001290052, NM_013282

CCDS: CCDS74262, CCDS74263

Canonical transcript exons

ENST00000650932 — 17 exons

Exon	Start	End
ENSE00003846893	4909501	4909655
ENSE00003888679	4944343	4944450
ENSE00003888837	4954350	4954488
ENSE00003888866	4950611	4950773
ENSE00003888878	4941528	4941628
ENSE00003889135	4932741	4932956
ENSE00003889750	4929222	4929476
ENSE00003890169	4950859	4950996
ENSE00003892389	4910876	4911038
ENSE00003893337	4941745	4941931
ENSE00003893615	4947105	4947211
ENSE00003894000	4954650	4954822
ENSE00003894092	4944132	4944255
ENSE00003894817	4945861	4945965
ENSE00003895083	4960657	4962154
ENSE00003895631	4930716	4930876
ENSE00003895811	4956709	4956813

Expression profiles

Bgee: expression breadth ubiquitous, 198 present calls, max score 99.85.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 24.5224 / max 1184.4159, expressed in 1502 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
173380	21.4805	1407
173382	2.4903	973
173383	0.5516	332

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
oocyte	CL:0000023	99.85	gold quality
secondary oocyte	CL:0000655	99.74	gold quality
thymus	UBERON:0002370	97.69	gold quality
ventricular zone	UBERON:0003053	95.83	gold quality
ganglionic eminence	UBERON:0004023	93.37	gold quality
buccal mucosa cell	CL:0002336	92.60	gold quality
trabecular bone tissue	UBERON:0002483	88.67	gold quality
ileal mucosa	UBERON:0000331	87.05	gold quality
bone marrow	UBERON:0002371	86.03	gold quality
stromal cell of endometrium	CL:0002255	81.88	gold quality
bone marrow cell	CL:0002092	81.56	gold quality
vermiform appendix	UBERON:0001154	79.55	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	77.93	gold quality
pancreatic ductal cell	CL:0002079	76.98	silver quality
lymph node	UBERON:0000029	76.70	gold quality
mucosa of transverse colon	UBERON:0004991	76.14	gold quality
caecum	UBERON:0001153	74.41	gold quality
esophagus squamous epithelium	UBERON:0006920	74.24	gold quality
esophagus mucosa	UBERON:0002469	74.16	gold quality
amniotic fluid	UBERON:0000173	73.06	gold quality
mucosa of sigmoid colon	UBERON:0004993	72.24	gold quality
tonsil	UBERON:0002372	71.46	gold quality
colonic mucosa	UBERON:0000317	71.24	gold quality
adrenal tissue	UBERON:0018303	70.81	gold quality
endometrium	UBERON:0001295	70.57	gold quality
gingival epithelium	UBERON:0001949	70.07	silver quality
oviduct epithelium	UBERON:0004804	69.85	silver quality
jejunal mucosa	UBERON:0000399	69.83	gold quality
gingiva	UBERON:0001828	69.56	gold quality
tibia	UBERON:0000979	69.28	gold quality

Single-cell (SCXA)

Detected in 15 experiment(s), a significant marker in 13.

Experiment	Marker?	Max mean expression
E-CURD-6	yes	1076.25
E-MTAB-9067	yes	667.61
E-MTAB-10432	yes	640.75
E-MTAB-6075	yes	525.37
E-GEOD-114530	yes	447.90
E-HCAD-6	yes	435.22
E-GEOD-93593	yes	424.65
E-MTAB-9435	yes	268.72
E-MTAB-8530	yes	141.83
E-CURD-112	yes	50.34
E-HCAD-4	yes	47.12
E-MTAB-6678	yes	8.61
E-ANND-3	yes	5.66
E-MTAB-6911	no	653.60
E-CURD-11	no	540.53

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

5 targets.

Target	Regulation
ABCB1	Repression
PPARG	Repression
RB1	Activation
TOP2A	Unknown
VEGFA	Unknown

Upstream regulators (CollecTRI, top): CEBPA, CEBPB, E2F1, KDM2B, NFYA, SP3, TP53, TP73

miRNA regulators (miRDB)

86 targeting UHRF1, 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-9-5P	100.00	72.28	2361
HSA-MIR-3689D	100.00	66.14	1181
HSA-MIR-6851-5P	100.00	65.63	1294
HSA-MIR-12118	100.00	65.88	1270
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-1184	99.99	68.19	1458
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-6891-5P	99.98	66.53	1372
HSA-MIR-3173-3P	99.98	66.49	1217
HSA-MIR-9718	99.94	68.91	918
HSA-MIR-4760-3P	99.93	70.50	2385
HSA-MIR-3119	99.92	71.34	2390
HSA-MIR-145-5P	99.92	71.13	1836
HSA-MIR-5195-3P	99.92	70.92	1877
HSA-MIR-652-5P	99.91	67.49	505
HSA-MIR-124-3P	99.89	73.74	3043
HSA-MIR-506-3P	99.89	73.55	3057
HSA-MIR-548D-3P	99.87	70.67	4362
HSA-MIR-548BB-3P	99.86	70.58	4354
HSA-MIR-579-3P	99.86	71.66	3628
HSA-MIR-548AC	99.84	70.77	4351
HSA-MIR-548H-3P	99.84	70.80	4349
HSA-MIR-548Z	99.84	70.80	4349
HSA-MIR-664B-3P	99.84	71.65	3590
HSA-MIR-4307	99.82	70.45	3374
HSA-MIR-374C-5P	99.80	72.06	2910
HSA-MIR-655-3P	99.80	72.19	2909
HSA-MIR-148A-3P	99.74	73.77	1700
HSA-MIR-148B-3P	99.74	73.75	1700
HSA-MIR-152-3P	99.74	73.75	1703

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 35.1% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• ICBP90 expression altered in cancer cell lines and upregulated by E2F-1 overexpression, with efficiency depending on cancer status of cell line (PMID:12838312)
• Apoptosis is dependent upon ICBP90 expression downregulation and ICBP90 exhibits anti-apoptotic properties. (PMID:15033738)
• ICBP90 is involved in cell proliferation by way of methylation-mediated regulation of certain genes. (PMID:15361834)
• ICBP90 down-regulation is a key event in G1 arrest preceding T cell death (PMID:15964557)
• ICBP90 overexpression is involved in the altered checkpoint controls occurring in cancerogenesis (PMID:16007129)
• General requirement for UHRF1 in tumor cell proliferation implicates the RING domain of UHRF1 as a functional determinant of growth regulation. (PMID:16195352)
• UHRF1 inhibits the late phase of oligodendrocyte differentiation. (PMID:17065439)
• These findings collectively indicate that the human NP95 gene is the functional orthologue of the murine Np95 gene. (PMID:17067204)
• data suggest that UHRF1 may help recruit DNMT1 to hemimethylated DNA to facilitate faithful maintenance of DNA methylation (PMID:17673620)
• A new role of ICBP90 in the relationship between histone ubiquitination and DNA methylation in the context of tumoral angiogenesis and tumour suppressor genes silencing. (PMID:17934516)
• ICBP90 is required for proper heterochromatin formation in mammalian cells (PMID:17967883)
• Parasite proliferation was suppressed in G1-arrested cells induced by UHRF1-siRNA, indicating the importance of the G2 phase via UHRF1-induced G1/S transition for T. gondii growth. (PMID:18005238)
• the 1.7 A crystal structure of the apo SRA domain of human UHRF1 and a 2.2 A structure of its complex with hemi-methylated DNA, revealing a previously unknown reading mechanism for methylated CpG sites (mCpG) (PMID:18772889)
• structural analysis and hemimethylated CpG binding of the SRA domain from human UHRF1 (PMID:18945682)
• UHRF1 recruited and cooperated with G9a to inhibit the p21 promoter activity, which correlated with the elevated p21 protein level in human UHRF1 siRNA-transfected HeLa cells. (PMID:19056828)
• UHRF1 may bring two components (histones and DNA) carrying appropriate markers (on the tails of H3 and hemimethylated CpG sites) ready to be assembled into a nucleosome after replication (PMID:19077538)
• role of UHRF1 in human cervical cancer cells as a negative regulator of radiosensitivity. (PMID:19270723)
• ICBP90 might be a pivotal target for the ERK1/2 signaling pathway to control the proliferation of Jurkat T cells. (PMID:19328461)
• Significant overexpression of UHRF1 was observed in bladder cancer. The overexpression was correlated with the stage and grade of the cancer. (PMID:19491893)
• Np95, Dnmt3a and Dnmt3b have regulatory roles in mediating epigenetic silencing through histone modification followed by DNA methylation (PMID:19798101)
• Tip60 is a novel partner of the epigenetic integration platform interplayed by UHRF1, DNMT1 and HDAC1 involved in the epigenetic code replication. (PMID:19800870)
• UHRF1 regulates BRCA1 transcription by inducing DNA methylation, histone modifications, and recruitment of transcriptional complex on the BRCA1 promoter in breast neoplasms. (PMID:19943104)
• Knockdown of UHRF1 activates MDR1 promoter activity and expression, attenuates the binding of UHRF1 and HDAC1 to the MDR1 promoter.Overexpression of UHRF1 in NCI/ADR-RES cells can induce deacetylation of histones H3 and H4 on the MDR1 promoter (PMID:20037778)
• results reveal that the disruption of Dnmt1/PCNA/UHRF1 interactions acts as an oncogenic event and that one of its signatures (i.e. the low level of mMTase activity) is a molecular biomarker associated with a poor prognosis in GBM patients (PMID:20613874)
• UHRF1 confers radioresistance to human breast cancer cells (PMID:21067293)
• Data suggest that UHRF1 links epigenetic regulation with DNA replication. UHRF1 depletion/knockdown leads to caspase 8-mediated apoptosis, cell cycle arrest, and cell death. UHRF1 accumulates rapidly at sites of DNA injury. (PMID:21214517)
• Findings suggest that, by balancing Dnmt1 ubiquitination, Usp7 and Uhrf1 fine tune Dnmt1 stability. (PMID:21268065)
• down-regulation of ICBP90 induced the descended expression of Topo IIalpha protein which is the target enzyme of doxorubicin (PMID:21296067)
• UHRF1 should be considered, along with DNMTs, among the potential targets for cancer treatment and/or therapeutic stratification. (PMID:21351083)
• Recognition of multivalent histone states associated with heterochromatin by UHRF1 protein. (PMID:21489993)
• the downregulation of UHRF1 in both breast cancer cell lines significantly inhibited the colony formation capacity. (PMID:21539450)
• High UHRF1 is associated with tumor recurrence in non-muscle-invasive bladder cancer. (PMID:21611839)
• PHD finger recognition of unmodified histone H3R2 links UHRF1 to regulation of euchromatic gene expression (PMID:21777816)
• the PHD domain of UHRF1 is an epigenetic regulatory module dedicated to the recognition of an unmodified arginine residue (R2) on histone H3 (PMID:21808300)
• The PHD finger of human UHRF1 reveals a new subgroup of unmethylated histone H3 tail readers. (PMID:22096602)
• UHRF1 PHD finger (including the preceding zinc-Cys4 knuckle) acts together with the adjacent double Tudor domain to specifically recognize the H3K9me3 mark. (PMID:22100450)
• High UHRF1 expression is associated with colorectal cancer. (PMID:22219067)
• The fusion of NRIP1 with UHRF1 involved in the unbalanced translocation between chromosomes 19 and 21 in a patient with an ALL-positive for a t(9;22) translocation. (PMID:22285022)
• UHRF1 coordinates peroxisome proliferator activated receptor gamma epigenetic silencing and mediates colorectal cancer progression. (PMID:22286757)
• Depletion of UHRF1 resulted in reactivation of several tumour suppressor genes. (PMID:22330138)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	uhrf1	ENSDARG00000103409
mus_musculus	Uhrf1	ENSMUSG00000001228
rattus_norvegicus	Uhrf1	ENSRNOG00000048411

Paralogs (2): UHRF2 (ENSG00000147854), SHISA5 (ENSG00000164054)

Protein

Protein identifiers

E3 ubiquitin-protein ligase UHRF1 — Q96T88 (reviewed: Q96T88)

Alternative names: Inverted CCAAT box-binding protein of 90 kDa, Nuclear zinc finger protein Np95, RING finger protein 106, Transcription factor ICBP90, Ubiquitin-like PHD and RING finger domain-containing protein 1

All UniProt accessions (4): Q96T88, A0A087WTW0, A0A087WVR3, A0A087WWG9

UniProt curated annotations — full annotation on UniProt →

Function. E3 ubiquitin-protein ligase that acts as a key epigenetic regulator by bridging DNA methylation and chromatin modification. Plays a key role in DNA methylation inheritance by promoting recruitment of DNMT1 to hemimethylated DNA and ensure faithful propagation of the DNA methylation patterns through DNA replication. Acts both as a histone reader and writer: specifically recognizes and binds (1) hemimethylated DNA at replication forks and (2) histone H3 trimethylated at ‘Lys-9’ and unmethylated at ‘Arg-2’ (H3K9me3 and H3R2me0, respectively), thereby activating its E3 ubiquitin-protein ligase activity. UHRF1 then mediates histone H3 ‘Lys-18’ monoubiquitination (H3K18ub), a docking site for DNMT1, leading to DNMT1 recruitment and replication-coupled DNA methylation maintenance. Also mediates histone H3 ‘Lys-14’ and ‘Lys-23’ ubiquitination (H3K14ub and H3K23ub) at lower level. Histone ubiquitin ligase activity also stimulates the methyltransferase activity of SUV39H1 and/or SUV39H2, promoting accumulation of H3K9me3 histone mark to reinformce heterochromatin state. Enriched in pericentric heterochromatin where it recruits different chromatin modifiers required for this chromatin replication. Also localizes to euchromatic regions where it negatively regulates transcription possibly by impacting DNA methylation and histone modifications. Plays a role in DNA repair by cooperating with UHRF2 to ensure recruitment of FANCD2 to interstrand cross-links (ICLs) leading to FANCD2 activation. Also ubiquitinates non-histone proteins, such as histone H3, KIF11 and PML. Acts as a critical player of proper spindle architecture by catalyzing the ‘Lys-63’-linked ubiquitination of KIF11, thereby controlling KIF11 localization on the spindle.

Subunit / interactions. Interacts with DNMT1; the interaction is direct. Interacts with DNMT3A and DNMT3B. Interacts with HDAC1, but not with HDAC2. Interacts with BLTP3A. Interacts with EHMT2. 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 UHRF2. Interacts with FANCD2. Interacts with TET1 isoform 2; this interaction induces the recruitment of TET1 isoform 2 to replicating heterochromatin.

Subcellular location. Nucleus. Chromosome.

Tissue specificity. Expressed in thymus, bone marrow, testis, lung and heart. Overexpressed in breast cancer.

Post-translational modifications. Phosphorylation at Ser-298 of the linker region by PKA decreases the binding to H3K9me3. Phosphorylation at Ser-639 by CDK1 during M phase impairs interaction with USP7, preventing deubiquitination and leading to degradation by the proteasome. Ubiquitinated; which leads to proteasomal degradation. Autoubiquitinated; interaction with USP7 leads to deubiquitination and prevents degradation. Ubiquitination and degradation takes place during M phase, when phosphorylation at Ser-639 prevents interaction with USP7 and subsequent deubiquitination. Polyubiquitination may be stimulated by DNA damage.

Disease relevance. Defects in UHRF1 may be a cause of cancers. Overexpressed in many different forms of human cancers, including bladder, breast, cervical, colorectal and prostate cancers, as well as pancreatic adenocarcinomas, rhabdomyosarcomas and gliomas. Plays an important role in the correlation of histone modification and gene silencing in cancer progression. Expression is associated with a poor prognosis in patients with various cancers, suggesting that it participates in cancer progression.

Domain organisation. The UBL domain is required for the E3 histone H3 ubiquitin-protein ligase activity: it binds the backside of UBE2D E2 ubiquitin-conjugating enzymes (UBE2D1, UBE2D2, UBE2D3 or UBE2D4) and coordinates with other domains that recognize epigenetic marks on DNA and histone H3 to direct ubiquitin to H3. The PHD-type zinc finger specifically recognizes and binds histone H3 unmethylated at ‘Arg-2’ (H3R2me0), while the tudor-like regions specifically recognize and bind histone H3 trimethylated at ‘Lys-9’ (H3K9me3). The tudor-like regions simultaneously recognizes H3K9me3 through a conserved aromatic cage in the first tudor-like subdomain and unmodified H3K4 (H3K4me0) within a groove between the tandem subdomains. The linker region plays a role in the formation of a histone H3-binding hole between the reader modules formed by the tudor-like regions and the PHD-type zinc finger by making extended contacts with the tandem tudor-like regions. The YDG domain (also named SRA domain) specifically recognizes and binds hemimethylated DNA at replication forks (DNA that is only methylated on the mother strand of replicating DNA). It contains a binding pocket that accommodates the 5-methylcytosine that is flipped out of the duplex DNA. 2 specialized loops reach through the resulting gap in the DNA from both the major and the minor grooves to read the other 3 bases of the CpG duplex. The major groove loop confers both specificity for the CpG dinucleotide and discrimination against methylation of deoxycytidine of the complementary strand. The YDG domain also recognizes and binds 5-hydroxymethylcytosine (5hmC).

Induction. Up-regulated in proliferating cells, and down-regulated in quiescent cells. Down-regulated upon adriamycin-induced DNA damage, in a p53/TP53 and CDKN1A-dependent way. Induced by E2F1 transcription factor.

Pathway. Protein modification; protein ubiquitination.

Isoforms (2)

UniProt ID	Names	Canonical?
Q96T88-1	1	yes
Q96T88-2	2

RefSeq proteins (5): NP_001041666, NP_001276979, NP_001276980, NP_001276981, NP_037414 (=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
IPR047406	Ubl_UHRF1	Domain

Pfam: PF00240, PF00628, PF02182, PF12148

UniProt features (191 total): strand 43, mutagenesis site 40, binding site 24, helix 21, turn 14, modified residue 13, region of interest 10, site 6, sequence variant 5, sequence conflict 4, cross-link 4, domain 2, zinc finger region 2, chain 1, compositionally biased region 1, splice variant 1

Structure

Experimental structures (PDB)

45 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
6W92	X-RAY DIFFRACTION	1.3
6VYJ	X-RAY DIFFRACTION	1.39
3ASL	X-RAY DIFFRACTION	1.41
3ZVZ	X-RAY DIFFRACTION	1.45
7FB7	X-RAY DIFFRACTION	1.45
8XV6	X-RAY DIFFRACTION	1.6
6B9M	X-RAY DIFFRACTION	1.68
6IIW	X-RAY DIFFRACTION	1.7
3BI7	X-RAY DIFFRACTION	1.7
5YYA	X-RAY DIFFRACTION	1.7
6VCS	X-RAY DIFFRACTION	1.7
3FL2	X-RAY DIFFRACTION	1.75
3SHB	X-RAY DIFFRACTION	1.8
3SOU	X-RAY DIFFRACTION	1.8
2PB7	X-RAY DIFFRACTION	1.9
3DWH	X-RAY DIFFRACTION	1.95
3T6R	X-RAY DIFFRACTION	1.95
3ZVY	X-RAY DIFFRACTION	1.95
3SOW	X-RAY DIFFRACTION	1.95
2FAZ	X-RAY DIFFRACTION	2
8XV8	X-RAY DIFFRACTION	2.05
3CLZ	X-RAY DIFFRACTION	2.2
5XPI	X-RAY DIFFRACTION	2.2
8XV7	X-RAY DIFFRACTION	2.25
4QQD	X-RAY DIFFRACTION	2.28
5C6D	X-RAY DIFFRACTION	2.29
3DB3	X-RAY DIFFRACTION	2.4
3DB4	X-RAY DIFFRACTION	2.4
8JIG	X-RAY DIFFRACTION	2.4
8WMS	X-RAY DIFFRACTION	2.4

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96T88-F1	80.53	0.48

Functional residue map

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

Catalytic / active sites (6): 316 (histone h3k4me0 binding); 327 (histone h3r2me0 binding); 330 (histone h3r2me0 binding); 479 (required to confer preferential recognition of cytosine over thymine); 489 (required to discriminate between hemimethylated dna versus symmetrically methylated dna); 491 (required for affinity and specificity for 5-mcpg sequence)

Ligand- & substrate-binding residues (24): 302; 305; 313; 316; 318; 319; 321; 333; 336; 341; 344; 360 …

Post-translational modifications (17): 76, 91, 95, 165, 287, 298, 368, 399, 546, 639, 651, 707, 709, 279, 385, 546, 670

Mutagenesis-validated functional residues (40):

Position	Phenotype
469	abolishes ability to bind hemimethylated dna.
489	abolishes specificity to hemimethylated dna.
491	decreased binding to methylated dna but does not affect ability to bind dna.
639	prevents phosphorylation by cdk1 during m phase, leading to increased stability.
639	mimics phosphorylation; impaired interaction with usp7, leading to decreased stability.
651	no effect on in vitro phosphorylation by pka.
666	no effect on in vitro phosphorylation by pka.
724–727	abolished e3 ubiquitin-protein ligase activity.
741	abolished e3 ubiquitin-protein ligase activity.
2	decreased histone h3 ubiquitin ligase activity.
6	strongly decreased histone h3 ubiquitin ligase activity.
8	strongly decreased histone h3 ubiquitin ligase activity.
46	strongly decreased histone h3 ubiquitin ligase activity.
48	strongly decreased histone h3 ubiquitin ligase activity.
50	decreased histone h3 ubiquitin ligase activity.
56	no effect on histone h3 ubiquitin ligase activity.
59	decreased histone h3 ubiquitin ligase activity.
62	no effect on histone h3 ubiquitin ligase activity.
64	strongly decreased histone h3 ubiquitin ligase activity.
65	decreased histone h3 ubiquitin ligase activity.
70	abolished binding to ube2d e2 ubiquitin conjugating enzymes, leading to strongly decreased histone h3 ubiquitin ligase a
72	no effect on histone h3 ubiquitin ligase activity.
142	impaired binding to histone h3 without affecting the protein folding; when associated with a-153.
145	impaired binding to histone h3.
147	reduced binding to h3k9me3.

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-5334118	DNA methylation
R-HSA-9821002	Chromatin modifications during the maternal to zygotic transition (MZT)

MSigDB gene sets: 390 (showing top): GOBP_CHROMOSOME_ORGANIZATION, HORIUCHI_WTAP_TARGETS_DN, PAL_PRMT5_TARGETS_UP, TTTGTAG_MIR520D, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, SHEPARD_BMYB_MORPHOLINO_DN, GTGCCTT_MIR506, WEI_MYCN_TARGETS_WITH_E_BOX, GOBP_NEGATIVE_REGULATION_OF_GENE_EXPRESSION_EPIGENETIC, GOBP_MITOTIC_SPINDLE_ASSEMBLY, GOBP_ORGANELLE_FISSION, LE_EGR2_TARGETS_UP, SHETH_LIVER_CANCER_VS_TXNIP_LOSS_PAM6, GOBP_PROTEIN_LOCALIZATION_TO_CHROMATIN, GOBP_PROTEIN_LOCALIZATION_TO_CHROMOSOME

GO Biological Process (19): negative regulation of transcription by RNA polymerase II (GO:0000122), double-strand break repair via homologous recombination (GO:0000724), ubiquitin-dependent protein catabolic process (GO:0006511), DNA damage response (GO:0006974), protein ubiquitination (GO:0016567), heterochromatin formation (GO:0031507), homologous recombination (GO:0035825), epigenetic regulation of gene expression (GO:0040029), negative regulation of gene expression via chromosomal CpG island methylation (GO:0044027), positive regulation of transcription by RNA polymerase II (GO:0045944), regulation of epithelial cell proliferation (GO:0050678), positive regulation of protein metabolic process (GO:0051247), protein autoubiquitination (GO:0051865), protein localization to chromatin (GO:0071168), mitotic spindle assembly (GO:0090307), chromosomal DNA methylation maintenance following DNA replication (GO:0141119), DNA repair (GO:0006281), chromatin organization (GO:0006325), response to stress (GO:0006950)

GO Molecular Function (19): cis-regulatory region sequence-specific DNA binding (GO:0000987), nucleic acid binding (GO:0003676), ubiquitin-protein transferase activity (GO:0004842), zinc ion binding (GO:0008270), methyl-CpG binding (GO:0008327), histone binding (GO:0042393), identical protein binding (GO:0042802), hemi-methylated DNA-binding (GO:0044729), ubiquitin protein ligase activity (GO:0061630), histone H3K9me2/3 reader activity (GO:0062072), histone H3K23 ubiquitin ligase activity (GO:0140234), histone H3K18 ubiquitin ligase activity (GO:0140248), DNA damage sensor activity (GO:0140612), histone H3K14 ubiquitin ligase activity (GO:0140851), histone H3 ubiquitin ligase activity (GO:0141055), DNA binding (GO:0003677), protein binding (GO:0005515), transferase activity (GO:0016740), metal ion binding (GO:0046872)

GO Cellular Component (8): chromatin (GO:0000785), euchromatin (GO:0000791), heterochromatin (GO:0000792), nucleus (GO:0005634), nucleoplasm (GO:0005654), replication fork (GO:0005657), spindle (GO:0005819), nuclear matrix (GO:0016363)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Epigenetic regulation of gene expression	1
Maternal to zygotic transition (MZT)	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
histone H3 ubiquitin ligase activity	3
regulation of transcription by RNA polymerase II	2
transcription by RNA polymerase II	2
protein ubiquitination	2
negative regulation of gene expression, epigenetic	2
binding	2
protein binding	2
chromosome	2
chromatin	2
nuclear lumen	2
negative regulation of DNA-templated transcription	1
recombinational repair	1
double-strand break repair	1
modification-dependent protein catabolic process	1
cellular response to stress	1
protein modification by small protein conjugation	1
cellular component assembly	1
heterochromatin boundary formation	1
heterochromatin organization	1
DNA recombination	1
chromatin remodeling	1
regulation of gene expression	1
positive regulation of DNA-templated transcription	1
regulation of cell population proliferation	1
epithelial cell proliferation	1
positive regulation of macromolecule metabolic process	1
protein metabolic process	1
regulation of protein metabolic process	1
protein localization to chromosome	1
mitotic sister chromatid segregation	1
mitotic spindle organization	1
spindle assembly	1
mitotic nuclear division	1
chromatin organization	1
DNA metabolic process	1
DNA damage response	1
cellular component organization	1
response to stimulus	1
transcription cis-regulatory region binding	1

Protein interactions and networks

STRING

2356 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
UHRF1	DNMT1	P26358	999
UHRF1	EHMT2	Q96KQ7	991
UHRF1	HDAC1	Q13547	980
UHRF1	DNMT3B	Q9UBC3	959
UHRF1	USP7	Q93009	918
UHRF1	TRIM28	Q13263	911
UHRF1	DNMT3A	Q9Y6K1	908
UHRF1	H3-3A	P06351	878
UHRF1	H3-5	Q6NXT2	878
UHRF1	H3-4	Q16695	876
UHRF1	H3C14	Q71DI3	875
UHRF1	H3C1	P02295	875
UHRF1	H3-7	Q5TEC6	875
UHRF1	KAT5	Q92993	832
UHRF1	DNMT3L	Q9UJW3	784
UHRF1	MECP2	P51608	784

IntAct

141 interactions, top by confidence:

A	B	Type	Score
CCDC22	VPS26C	psi-mi:“MI:0914”(association)	0.790
UHRF1	DNMT1	psi-mi:“MI:0915”(physical association)	0.700
UHRF1	DNMT1	psi-mi:“MI:0914”(association)	0.700
UHRF1	DNMT1	psi-mi:“MI:0403”(colocalization)	0.700
DNMT1	UHRF1	psi-mi:“MI:0403”(colocalization)	0.700
UQCRB	COX7A2L	psi-mi:“MI:0914”(association)	0.640
KPNA1	TCERG1	psi-mi:“MI:0914”(association)	0.640
H2BC1	PPM1G	psi-mi:“MI:0914”(association)	0.640
HDAC1	DNMT1	psi-mi:“MI:0914”(association)	0.600
DNMT1	HDAC1	psi-mi:“MI:0914”(association)	0.600
UHRF1	DNMT3B	psi-mi:“MI:0915”(physical association)	0.590
DNMT3A	UHRF1	psi-mi:“MI:0915”(physical association)	0.590
DNMT3B	UHRF1	psi-mi:“MI:0915”(physical association)	0.590
UHRF1	DNMT3A	psi-mi:“MI:0915”(physical association)	0.590

BioGRID (512): UHRF1 (Protein-peptide), HIST3H3 (Protein-peptide), UHRF1 (Affinity Capture-MS), UHRF1 (Affinity Capture-Western), MBD4 (Affinity Capture-Western), UHRF1 (Affinity Capture-Western), UHRF1 (Reconstituted Complex), MBD4 (Reconstituted Complex), UHRF1 (Affinity Capture-MS), UHRF1 (Affinity Capture-MS), UHRF1 (Affinity Capture-Western), UHRF1 (Reconstituted Complex), UHRF1 (Affinity Capture-MS), UHRF1 (Affinity Capture-MS), UHRF1 (Affinity Capture-MS)

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

10 interactions.

A	Effect	B	Mechanism
CSNK1D	up-regulates	UHRF1	phosphorylation
UHRF1	“down-regulates quantity by repression”	ABCB1	“transcriptional regulation”
Ub:E2	“up-regulates activity”	UHRF1	ubiquitination
UHRF1	“down-regulates activity”	RIF1	polyubiquitination
PIM1	“down-regulates quantity by destabilization”	UHRF1	phosphorylation
UHRF1	“down-regulates activity”	LRIF1	ubiquitination
KDM2B	“down-regulates quantity by repression”	UHRF1	“transcriptional regulation”
“Noncanonical PRC1”	“down-regulates quantity by repression”	UHRF1	“transcriptional regulation”
CyclinB/CDK1	“down-regulates quantity by destabilization”	UHRF1	phosphorylation
CDK2	“down-regulates quantity by destabilization”	UHRF1	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 155 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
DNA methylation	7	12.1×	6e-04
Defective pyroptosis	7	10.6×	8e-04
PRC2 methylates histones and DNA	7	10.3×	8e-04
E3 ubiquitin ligases ubiquitinate target proteins	5	9.4×	1e-02
NoRC negatively regulates rRNA expression	9	9.2×	4e-04
TP53 Regulates Transcription of DNA Repair Genes	5	8.8×	1e-02
Influenza Infection	5	8.5×	1e-02
FXIIa activates plasma kallikrein-kinin system	5	8.4×	1e-02

GO biological processes:

GO term	Partners	Fold	FDR
nucleosome assembly	9	9.4×	6e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	51
Likely benign	3
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

2970 predictions. Top by Δscore:

Variant	Effect	Δscore
19:4910874:A:AG	acceptor_gain	1.0000
19:4910875:G:GG	acceptor_gain	1.0000
19:4910875:GC:G	acceptor_gain	1.0000
19:4910875:GCGCC:G	acceptor_gain	1.0000
19:4911035:ACAGG:A	donor_loss	1.0000
19:4911036:CAGGT:C	donor_loss	1.0000
19:4911037:AGGTA:A	donor_loss	1.0000
19:4911038:GGTA:G	donor_loss	1.0000
19:4911039:G:A	donor_loss	1.0000
19:4911040:T:A	donor_loss	1.0000
19:4929218:GCA:G	acceptor_loss	1.0000
19:4929220:A:AG	acceptor_gain	1.0000
19:4929220:A:AT	acceptor_loss	1.0000
19:4929220:AGAT:A	acceptor_gain	1.0000
19:4929220:AGATG:A	acceptor_gain	1.0000
19:4929221:G:GT	acceptor_gain	1.0000
19:4929221:GA:G	acceptor_gain	1.0000
19:4929221:GAT:G	acceptor_gain	1.0000
19:4929221:GATG:G	acceptor_gain	1.0000
19:4929221:GATGG:G	acceptor_gain	1.0000
19:4929472:ACAAG:A	donor_loss	1.0000
19:4929473:CAAGG:C	donor_loss	1.0000
19:4929475:AGGT:A	donor_loss	1.0000
19:4929476:GGTG:G	donor_loss	1.0000
19:4929477:G:A	donor_loss	1.0000
19:4929478:T:G	donor_loss	1.0000
19:4930711:CACA:C	acceptor_loss	1.0000
19:4930714:AGGT:A	acceptor_loss	1.0000
19:4930715:G:GA	acceptor_loss	1.0000
19:4930872:GACGA:G	donor_gain	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000145592 (19:4942741 T>C), RS1000174559 (19:4943118 T>A,C), RS1000175730 (19:4942543 G>T), RS1000177662 (19:4923484 T>TTGGCTGCCCC), RS1000199938 (19:4912238 G>A,C), RS1000322379 (19:4907334 A>T), RS1000393418 (19:4916903 G>A), RS1000438138 (19:4906904 G>A,C), RS1000441194 (19:4953041 C>T), RS1000456832 (19:4922307 C>T), RS1000482174 (19:4943501 C>CA,CG,CT), RS1000498571 (19:4911405 C>T), RS1000543360 (19:4942437 G>A), RS1000549901 (19:4912919 C>G), RS1000570242 (19:4946745 T>C)

Disease associations

OMIM: gene MIM:607990 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
DNA repair disease	Moderate	Autosomal recessive
immunodeficiency-centromeric instability-facial anomalies syndrome	Limited	Autosomal recessive

Mondo (2): DNA repair disease (MONDO:0021190), immunodeficiency-centromeric instability-facial anomalies syndrome (MONDO:0000133)

Orphanet (0):

HPO phenotypes

23 total (23 of 23 shown, HPO-id order):

HPO	Term
HP:0000158	Macroglossia
HP:0000256	Macrocephaly
HP:0000286	Epicanthus
HP:0000316	Hypertelorism
HP:0000347	Micrognathia
HP:0000369	Low-set ears
HP:0001249	Intellectual disability
HP:0001263	Global developmental delay
HP:0001334	Communicating hydrocephalus
HP:0001537	Umbilical hernia
HP:0001874	Abnormality of neutrophils
HP:0001888	Decreased total lymphocyte count
HP:0001903	Anemia
HP:0002024	Malabsorption
HP:0002205	Recurrent respiratory infections
HP:0002721	Immunodeficiency
HP:0003220	Abnormality of chromosome stability
HP:0004313	Decreased circulating immunoglobulin concentration
HP:0004322	Short stature
HP:0005280	Depressed nasal bridge
HP:0005374	Cellular immunodeficiency
HP:0010808	Protruding tongue
HP:0012368	Flat face

GWAS associations

12 associations (top):

Study	Trait	p-value
GCST007267_12	Systolic blood pressure	1.000000e-12
GCST007930_139	Medication use (agents acting on the renin-angiotensin system)	5.000000e-11
GCST008362_27	Birth weight	8.000000e-11
GCST008550_32	Mental health study participation (completed survey)	3.000000e-08
GCST008972_7	Urate levels	9.000000e-12
GCST009379_227	Type 2 diabetes	3.000000e-09
GCST90000025_671	Appendicular lean mass	2.000000e-29
GCST90000047_234	Age at first sexual intercourse	1.000000e-08
GCST90020028_1642	Hip circumference adjusted for BMI	5.000000e-12
GCST90020028_1643	Hip circumference adjusted for BMI	6.000000e-09
GCST90020028_1644	Hip circumference adjusted for BMI	1.000000e-09
GCST90020028_1645	Hip circumference adjusted for BMI	3.000000e-08

EFO canonical traits (8, from GWAS)

EFO ID	Trait name
EFO:0006335	systolic blood pressure
EFO:0009931	Agents acting on the renin-angiotensin system use measurement
EFO:0004344	birth weight
EFO:0010130	health study participation
EFO:0004531	urate measurement
EFO:0004980	appendicular lean mass
EFO:0009749	age at first sexual intercourse measurement
EFO:0008039	BMI-adjusted hip circumference

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D049914	DNA Repair-Deficiency Disorders	C18.452.284
C537362	Immunodeficiency syndrome, variable (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2424510 (SINGLE PROTEIN)

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs2261988	ARRDC5, UHRF1		0.00	0

ChEMBL bioactivities

4 potent at pChembl≥5 of 30 total, top 4 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
5.62	IC50	2371	nM	CHEMBL1611255
5.04	IC50	9067	nM	CHEMBL1725136
5.02	IC50	9638	nM	CHEMBL1484425
5.00	EC50	1e+04	nM	CHEMBL5286019

PubChem BioAssay actives

1 with measured affinity, of 155 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
2,4-dimethylpyridine	1987092: Inhibition of UHRF1 (unknown origin) by AlphaScreen assay	ec50	10.0000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	decreases expression, decreases methylation, increases expression, increases mutagenesis	8
sodium arsenite	affects expression, decreases expression, increases abundance, increases expression	7
Valproic Acid	increases methylation, affects cotreatment, increases expression	6
bisphenol A	decreases expression, increases expression, affects expression	5
Estradiol	increases expression	5
Aflatoxin B1	increases expression, affects methylation, decreases expression	3
Cadmium Chloride	increases abundance, increases palmitoylation, decreases expression, increases expression, decreases reaction	3
perfluorooctanoic acid	decreases expression	2
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	increases expression, affects cotreatment	2
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	decreases expression	2
Resveratrol	affects cotreatment, increases expression, decreases expression	2
Arsenic Trioxide	increases expression, decreases expression	2
Air Pollutants	increases oxidation, decreases expression, affects cotreatment, increases abundance	2
Cisplatin	affects cotreatment, decreases expression, increases expression	2
Folic Acid	affects cotreatment, decreases expression	2
Nickel	increases expression	2
Niclosamide	decreases expression	2
Tetrachlorodibenzodioxin	decreases expression, increases expression	2
Tretinoin	affects expression, decreases expression	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	2
GSK-J4	decreases expression	1
afuresertib	decreases expression	1
FR900359	affects phosphorylation	1
TAK-243	increases sumoylation	1
lasiocarpine	increases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	increases oxidation, increases abundance, affects cotreatment	1
nobiletin	decreases expression, decreases reaction	1
sodium arsenate	decreases expression, decreases reaction	1
terbufos	increases methylation	1

ChEMBL screening assays

36 unique, capped per target: 36 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL2429073	Binding	Inhibition of UHRF1 (unknown origin) after 30 mins by AlphaScreen assay	Small-molecule ligands of methyl-lysine binding proteins: optimization of selectivity for L3MBTL3. — J Med Chem

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B8RI	Abcam HCT 116 UHRF1 KO	Cancer cell line	Male
CVCL_B9TX	Abcam A-549 UHRF1 KO	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT02912559	PHASE3	ACTIVE_NOT_RECRUITING	Combination Chemotherapy With or Without Atezolizumab in Treating Patients With Stage III Colon Cancer and Deficient DNA Mismatch Repair
NCT03236935	PHASE1	COMPLETED	Phase Ib of L-NMMA and Pembrolizumab
NCT07408583	PHASE1/PHASE2	NOT_YET_RECRUITING	Prenatal Transplantation for Fetuses With Fanconi Anemia
NCT05484570	Not specified	RECRUITING	Natural History Study for DNA Repair Disorders