Muut nimet: ICBP90, Np95, RNF106, TDRD22, hNP95, hUHRF1, huNp95.
https://www.ncbi.nlm.nih.gov/gene/29128
Summary 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 (HDAC) 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] Expression Broad expression in bone marrow (RPKM 7.7), lymph node (RPKM 6.3) and 14 other tissues See more
- Preferred Names
- E3 ubiquitin-protein ligase UHRF1
- Names
- RING finger protein 106
- RING-type E3 ubiquitin transferase UHRF1
- inverted CCAAT box-binding protein of 90 kDa
- nuclear phosphoprotein 95
- nuclear protein 95
- nuclear zinc finger protein Np95
- transcription factor ICBP90
- ubiquitin-like PHD and RING finger domain-containing protein
Homo sapiens ubiquitin like with PHD and ring finger domains 1 (UHRF1), transcript variant 1, mRNA
NCBI Reference Sequence: NM_001048201.3
- Conserved Domains (6) summary
-
- cd01797
Location:1 → 78 - NIRF_N; amino-terminal ubiquitin-like domain of Np95 and NIRF
- smart00213
Location:3 → 74 - UBQ; Ubiquitin homologues
- cd00162
Location:724 → 766 - RING; RING-finger (Really
Interesting New Gene) domain, a specialized type of Zn-finger of 40 to
60 residues that binds two atoms of zinc; defined by the 'cross-brace'
motif C-X2-C-X(9-39)-C-X(1-3)- H-X(2-3)-(N/C/H)-X2-C-X(4-48)C-X2-C;
probably involved in ...
mediating protein-protein interactions; identified in a proteins with a wide range of functions such as viral replication, signal transduction, and development; has two variants, the C3HC4-type and a C3H2C3-type (RING-H2 finger), which have different cysteine/histidine pattern; a subset of RINGs are associated with B-Boxes (C-X2-H-X7-C-X7-C-X2-C-H-X2-H)
- cd15616
Location:317 → 363 - PHD_UHRF1; PHD finger found in ubiquitin-like PHD and RING finger domain-containing protein 1 (UHRF1). UHRF1 (also termed inverted CCAAT box-binding protein of 90 kDa, nuclear protein 95, nuclear zinc finger protein Np95 (Np95), RING finger protein 106, transcription factor ICBP90, or E3 ubiquitin-protein ligase UHRF1) is a unique chromatin effector protein that integrates the recognition of both histone PTMs and DNA methylation. It is essential for cell proliferation and plays a critical role in the development and progression of many human carcinomas, such as laryngeal squamous cell carcinoma (LSCC), gastric cancer (GC), esophageal squamous cell carcinoma (ESCC), colorectal cancer, prostate cancer, and breast cancer. UHRF1 acts as a transcriptional repressor through its binding to histone H3 when it is unmodified at Arg2. Its overexpression in human lung fibroblasts results in downregulation of expression of the tumour suppressor pRB. It also plays a role in transcriptional repression of the cell cycle regulator p21. Moreover, UHRF1-dependent repression of transcription factors can facilitate the G1-S transition. It interacts with Tat-interacting protein of 60 kDa (TIP60) and induces degradation-independent ubiquitination of TIP60. It is also an N-methylpurine DNA glycosylase (MPG)-interacting protein that binds MPG in a p53 status-independent manner in the DNA base excision repair (BER) pathway. In addition, UHRF1 functions as an epigenetic regulator that is important for multiple aspects of epigenetic regulation, including maintenance of DNA methylation patterns and recognition of various histone modifications. UHRF1 contains an N-terminal ubiquitin-like domain (UBL), a tandem Tudor domain (TTD), a plant homeodomain (PHD) finger, a SET and RING finger associated (SRA) domain, and a C-terminal RING-finger domain. It specifically binds to hemimethylated DNA, double-stranded CpG dinucleotides, and recruits the maintenance methyltransferase DNMT1 to its hemimethylated DNA substrate through its SRA domain. UHRF1-dependent H3K23 ubiquitylation has an essential role in maintaining DNA methylation and replication. The tandem Tudor domain directs UHRF1 binding to the heterochromatin mark histone H3K9me3 and the PHD finger targets UHRF1 to unmodified histone H3 in euchromatic regions. The RING-finger domain exhibit both autocatalytic E3 ubiquitin (Ub) ligase activity and activity against histone H3 and DNMT1.
- pfam02182
Location:417 → 584 - SAD_SRA; SAD/SRA domain. The domain goes by several names including SAD, SRA and YDG. It adopts a beta barrel, modified PUA-like, fold that is widely present in eukaryotic chromatin proteins and in bacteria. Versions of this domain are known to bind hemi-methylated CpG dinucleotides and also other 5mC containing dinucleotides. The domain binds DNA by flipping out the methylated cytosine base from the DNA double helix.The conserved tyrosine and aspartate residues and a glycine rich patch are critical for recognition of the flipped out base. Mammalian UHRF1 that contains this domain plays an important role in maintenance of methylation at CpG dinucleotides by recruiting DNMT1 to hemimethylated sites associated with replication forks. The SAD/SRA domain has been combined with other domains involved in the ubiquitin pathway on multiple occasions and such proteins link recognition of DNA methylation to chromatin-protein ubiquitination. The domain is also found in species that lack DNA methylation, such as certain apicomplexans, suggestive of other DNA-binding modes or functions. A highly derived and distinct version of the domain is also found in fungi where it is fused to AlkB-type 2OGFeDO domains. In bacteria, the domain is usually fused or associated with restriction endonucleases, many of which target methylated or hemi-methylated DNA.
- pfam12148
Location:133 → 284 - TTD; Tandem tudor domain within UHRF1 preferentially binds H3 histone tails trimethylated at Lys-9. It specifically recognizes H3 tail peptides with the heterochromatin-associated modification state of trimethylated lysine 9 and unmodified lysine 4 (H3K4me0/K9me3). This domain is found in eukaryotes and is found in association with pfam00097, pfam02182, pfam00628, pfam00240.
- cd01797
- A Bifunctional Role for the UHRF1 UBL Domain in the Control of Hemi-methylated DNA-Dependent Histone Ubiquitylation. DaRosa PA, et al. Mol Cell, 2018 Nov 15. PMID 30392931,
- ICBP90 mediates Notch signaling to facilitate human hepatocellular carcinoma growth. Fu H, et al. Tissue Cell, 2018 Oct. PMID 30309512
- Biochemical and dynamic basis for combinatorial recognition of H3R2K9me2 by dual domains of UHRF1. Abhishek S, et al. Biochimie, 2018 Jun. PMID 29656054
- Upregulation of UHRF1 promotes the progression of melanoma by inducing cell proliferation. Wei C, et al. Oncol Rep, 2018 Jun. PMID 29620240, Free PMC Article
- Overexpression of UHRF1 promotes silencing of tumor suppressor genes and predicts outcome in hepatoblastoma. Beck A, et al. Clin Epigenetics, 2018. PMID 29507645, Free PMC Article
GeneRIFs: Gene References Into Functions
- The UBL coordinates with other UHRF1 domains that recognize epigenetic marks on DNA and histone H3 to direct ubiquitin to H3. Results show UBLs from other E3s also have a conserved interaction with the E2, Ube2D, highlighting a potential prevalence of interactions between UBLs and E2s.
- Findings suggest that UHRF1 is critical for aberrant tumor suppressor genes silencing and sustained growth signaling in hepatoblastoma and that UHRF1 overexpression levels might serve as a prognostic biomarker.
- Our novel findings strongly indicate that inactivation of the Notch signaling pathway impedes hepatocellular carcinoma progress via reduction of ICBP90.
- Using an integrative approach that combines small angle X-ray scattering, NMR spectroscopy, and molecular dynamics simulations, we characterized the dynamics of the tandem tudor domain-plant homeodomain (TTD-PHD) histone reader module, including its 20-residue interdomain linker.
- UHRF1 deficiency leads to the induction of EMT by activating the CXCR4/AKT-JNK/IL-6 signaling pathway, thereby contributing to the expansion of cancer stem-like cells
- studies support a noncompetitive model for UHRF1 and DNMT1 chromatin recruitment to replicating chromatin and define a role for hemimethylated linker DNA as a regulator of UHRF1 ubiquitin ligase substrate selectivity.
- Lys4 methylation on H3 peptide has an insignificant effect on combinatorial recognition of R2 and K9me2 on H3 by the UHRF1 TTD-PHD. We propose that subtle variations of key residues at the binding pocket determine status specific recognition of histone methyl-lysines by the reader domains.
- Study provides evidence that elevated expression of UHRF1 plays an important role in melanoma cell proliferation and progression, and it can be used as a prognostic biomarker for melanoma.
- Our data demonstrate for the first time that TIP60 through its MYST domain directly interacts with UHRF1
- Findings confirmed that UHRF1 is a gene driver in medulloblastoma (MB) and, revealed that UHRF1 is in a modulation axis downstream of miR-378. Its promoter region is targeted by miR-378 which negatively regulates its expression in MB cells.
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