Description: Homo sapiens ubiquitin-like with PHD and ring finger domains 1 (UHRF1), transcript variant 2, mRNA. RefSeq Summary (NM_013282): 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. [provided by RefSeq, Feb 2014]. Transcript (Including UTRs) Position: hg19 chr19:4,910,566-4,962,165 Size: 51,600 Total Exon Count: 17 Strand: + Coding Region Position: hg19 chr19:4,910,859-4,960,814 Size: 49,956 Coding Exon Count: 17
ID:UHRF1_HUMAN DESCRIPTION: RecName: Full=E3 ubiquitin-protein ligase UHRF1; EC=6.3.2.-; AltName: Full=Inverted CCAAT box-binding protein of 90 kDa; AltName: Full=Nuclear protein 95; AltName: Full=Nuclear zinc finger protein Np95; Short=HuNp95; Short=hNp95; AltName: Full=RING finger protein 106; AltName: Full=Transcription factor ICBP90; AltName: Full=Ubiquitin-like PHD and RING finger domain-containing protein 1; Short=hUHRF1; AltName: Full=Ubiquitin-like-containing PHD and RING finger domains protein 1; FUNCTION: Multidomain protein that acts as a key epigenetic regulator by bridging DNA methylation and chromatin modification. Specifically recognizes and binds hemimethylated DNA at replication forks via its YDG domain and recruits DNMT1 methyltransferase to ensure faithful propagation of the DNA methylation patterns through DNA replication. In addition to its role in maintenance of DNA methylation, also plays a key role in chromatin modification: through its tudor-like regions and PHD- type zinc fingers, specifically recognizes and binds histone H3 trimethylated at 'Lys-9' (H3K9me3) and unmethylated at 'Arg-2' (H3R2me0), respectively, and recruits chromatin proteins. 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. Has E3 ubiquitin-protein ligase activity by mediating the ubiquitination of target proteins such as histone H3 and PML. It is still unclear how E3 ubiquitin-protein ligase activity is related to its role in chromatin in vivo. May be involved in DNA repair. PATHWAY: Protein modification; protein ubiquitination. SUBUNIT: Interacts with DNMT3A and DNMT3B (By similarity). Interacts with DNMT1; the interaction is direct. Interacts with USP7; leading to its deubiquitination. Interacts with histone H3. Interacts with HDAC1, but not with HDAC2. Interacts with UHRF1BP1. Interacts with PML. Interacts with EHMT2. Binds hemimethylated CpG containing oligonucleotides. INTERACTION: P26358:DNMT1; NbExp=10; IntAct=EBI-1548946, EBI-719459; SUBCELLULAR LOCATION: Nucleus. Note=Localizes to replication foci. Enriched in pericentric heterochromatin. Also localizes to euchromatic regions. TISSUE SPECIFICITY: Expressed in thymus, bone marrow, testis, lung and heart. Overexpressed in breast cancer. DEVELOPMENTAL STAGE: Expressed in fetal thymus, liver and kidney. 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. DOMAIN: The tudor-like regions specifically recognize and bind histone H3 unmethylated at 'Arg-2' (H3R2me0), while the PHD-type zinc finger specifically recognizes and binds 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 (PubMed:21489993, PubMed:21777816 and PubMed:22100450). 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 (PubMed:22837395). DOMAIN: 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) (PubMed:17673620). 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 (PubMed:18772889). The YDG domain also recognizes and binds 5-hydroxymethylcytosine (5hmC) (PubMed:21731699). DOMAIN: The RING finger is required for ubiquitin ligase activity (By similarity). PTM: Phosphorylation at Ser-298 of the linker region 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. PTM: 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 intereaction with USP7 and subsequent deubiquitination. Polyubiquitination may be stimulated by DNA damage. DISEASE: Note=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. SIMILARITY: Contains 1 PHD-type zinc finger. SIMILARITY: Contains 1 RING-type zinc finger. SIMILARITY: Contains 1 ubiquitin-like domain. SIMILARITY: Contains 1 YDG domain. SEQUENCE CAUTION: Sequence=BAB15177.1; Type=Erroneous initiation; WEB RESOURCE: Name=NIEHS-SNPs; URL="http://egp.gs.washington.edu/data/uhrf1/";
The RNAfold program from the Vienna RNA Package is used to perform the secondary structure predictions and folding calculations. The estimated folding energy is in kcal/mol. The more negative the energy, the more secondary structure the RNA is likely to have.
ModBase Predicted Comparative 3D Structure on Q96T88
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Orthologous Genes in Other Species
Orthologies between human, mouse, and rat are computed by taking the best BLASTP hit, and filtering out non-syntenic hits. For more distant species reciprocal-best BLASTP hits are used. Note that the absence of an ortholog in the table below may reflect incomplete annotations in the other species rather than a true absence of the orthologous gene.
Gene Ontology (GO) Annotations with Structured Vocabulary
Molecular Function: GO:0000987 core promoter proximal region sequence-specific DNA binding GO:0003677 DNA binding GO:0003700 transcription factor activity, sequence-specific DNA binding GO:0004842 ubiquitin-protein transferase activity GO:0005515 protein binding GO:0008270 zinc ion binding GO:0008327 methyl-CpG binding GO:0016740 transferase activity GO:0031493 nucleosomal histone binding GO:0035064 methylated histone binding GO:0042393 histone binding GO:0042802 identical protein binding GO:0044729 hemi-methylated DNA-binding GO:0046872 metal ion binding GO:0061630 ubiquitin protein ligase activity
Biological Process: GO:0000122 negative regulation of transcription from RNA polymerase II promoter GO:0006281 DNA repair GO:0006325 chromatin organization GO:0006351 transcription, DNA-templated GO:0006355 regulation of transcription, DNA-templated GO:0006511 ubiquitin-dependent protein catabolic process GO:0006974 cellular response to DNA damage stimulus GO:0007049 cell cycle GO:0008283 cell proliferation GO:0010216 maintenance of DNA methylation GO:0010390 histone monoubiquitination GO:0016567 protein ubiquitination GO:0016574 histone ubiquitination GO:0032270 positive regulation of cellular protein metabolic process GO:0045944 positive regulation of transcription from RNA polymerase II promoter GO:0051865 protein autoubiquitination GO:0090308 regulation of methylation-dependent chromatin silencing GO:2000373 positive regulation of DNA topoisomerase (ATP-hydrolyzing) activity
US Server
