Q8VDF2 · UHRF1_MOUSE
- ProteinE3 ubiquitin-protein ligase UHRF1
- GeneUhrf1
- StatusUniProtKB reviewed (Swiss-Prot)
- Organism
- Amino acids782 (go to sequence)
- Protein existenceEvidence at protein level
- Annotation score5/5
Function
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. Plays a role in DNA repair by cooperating with UHRF2 to ensure recruitment of FANCD2 to interstrand cross-links (ICLs) leading to FANCD2 activation. Plays a pivotal role in the establishment of correct spindle architecture by catalyzing the 'Lys-63'-linked ubiquitination of KIF11, thereby controlling KIF11 localization on the spindle.
Catalytic activity
Pathway
Protein modification; protein ubiquitination.
Features
Showing features for site, binding site.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Site | 321 | Histone H3K4me0 binding | ||||
Sequence: C | ||||||
Site | 332 | Histone H3R2me0 binding | ||||
Sequence: P | ||||||
Site | 335 | Histone H3R2me0 binding | ||||
Sequence: Q | ||||||
Binding site | 468-469 | 5-methylcytosine group (UniProtKB | ChEBI) of DNA (UniProtKB | ChEBI) | ||||
Sequence: AG | ||||||
Binding site | 474 | 5-methylcytosine group (UniProtKB | ChEBI) of DNA (UniProtKB | ChEBI) | ||||
Sequence: D | ||||||
Site | 484 | Required to confer preferential recognition of cytosine over thymine | ||||
Sequence: T | ||||||
Site | 494 | Required to discriminate between hemimethylated DNA versus symmetrically methylated DNA | ||||
Sequence: N | ||||||
Site | 496 | Required for affinity and specificity for 5-mCpG sequence | ||||
Sequence: R |
GO annotations
Keywords
- Molecular function
- Biological process
- Ligand
Enzyme and pathway databases
Names & Taxonomy
Protein names
- Recommended nameE3 ubiquitin-protein ligase UHRF1
- EC number
- Alternative names
Gene names
Organism names
- Organism
- Strains
- Taxonomic lineageEukaryota > Metazoa > Chordata > Craniata > Vertebrata > Euteleostomi > Mammalia > Eutheria > Euarchontoglires > Glires > Rodentia > Myomorpha > Muroidea > Muridae > Murinae > Mus > Mus
Accessions
- Primary accessionQ8VDF2
- Secondary accessions
Proteomes
Organism-specific databases
Subcellular Location
UniProt Annotation
GO Annotation
Note: Associated, through the YDG domain (also called SRA domain), with replicating DNA from early to late S phase, including at replicating pericentric heterochromatin (PubMed:36056023).
Also localizes to euchromatic regions. In non-S-phase cells, homogenously distributed through the nucleus (PubMed:36056023).
Also localizes to euchromatic regions. In non-S-phase cells, homogenously distributed through the nucleus (PubMed:36056023).
Keywords
- Cellular component
Phenotypes & Variants
Disruption phenotype
Mice display a sensitization to DNA damage and replication block, and die in mid-gestation.
Features
Showing features for mutagenesis.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Mutagenesis | 148 | Abolishes binding to histone H3K9me3 and ability to repress transcription of target genes. | ||||
Sequence: F → A | ||||||
Mutagenesis | 730 | Abolishes enzymatic activity. | ||||
Sequence: H → A |
Variants
We now provide the "Disease & Variants" viewer in its own tab.
The viewer provides 40 variants from UniProt as well as other sources including ClinVar and dbSNP.
PTM/Processing
Features
Showing features for chain, modified residue, cross-link.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Chain | PRO_0000056145 | 1-782 | E3 ubiquitin-protein ligase UHRF1 | |||
Sequence: MWIQVRTMDGKETHTVNSLSRLTKVQELRKKIEEVFHVEPQLQRLFYRGKQMEDGHTLFDYDVRLNDTIQLLVRQSLALPLSTKERDSELSDSDSGYGVGHSESDKSSTHGEGAAEADDKTVWEDTDLGLYKVNEYVDVRDNIFGAWFEAQVVQVQKRALSEDEPCSSSAVKTSEDDIMYHVKYDDYPEHGVDIVKAKNVRARARTVIPWENLEVGQVVMANYNVDYPRKRGFWYDVEICRKRQTRTARELYGNIRLLNDSQLNNCRIMFVDEVLMIELPKERRPLIASPSQPPPALRNTGKSGPSCRFCKDDENKPCRKCACHVCGGREAPEKQLLCDECDMAFHLYCLKPPLTSVPPEPEWYCPSCRTDSSEVVQAGEKLKESKKKAKMASATSSSRRDWGKGMACVGRTTECTIVPANHFGPIPGVPVGTMWRFRVQVSESGVHRPHVAGIHGRSNDGAYSLVLAGGYEDDVDNGNYFTYTGSGGRDLSGNKRTAGQSSDQKLTNNNRALALNCHSPINEKGAEAEDWRQGKPVRVVRNMKGGKHSKYAPAEGNRYDGIYKVVKYWPERGKSGFLVWRYLLRRDDTEPEPWTREGKDRTRQLGLTMQYPEGYLEALANKEKSRKRPAKALEQGPSSSKTGKSKQKSTGPTLSSPRASKKSKLEPYTLSEQQANLIKEDKGNAKLWDDVLTSLQDGPYQIFLSKVKEAFQCICCQELVFRPVTTVCQHNVCKDCLDRSFRAQVFSCPACRFELDHSSPTRVNQPLQTILNQLFPGYGSGR | ||||||
Modified residue | 76 | Phosphoserine | ||||
Sequence: S | ||||||
Modified residue | 91 | Phosphoserine | ||||
Sequence: S | ||||||
Modified residue | 93 | Phosphoserine | ||||
Sequence: S | ||||||
Modified residue | 95 | Phosphoserine | ||||
Sequence: S | ||||||
Modified residue | 161 | Phosphoserine | ||||
Sequence: S | ||||||
Modified residue | 303 | Phosphoserine; by PKA | ||||
Sequence: S | ||||||
Modified residue | 373 | Phosphoserine | ||||
Sequence: S | ||||||
Cross-link | 390 | Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO2) | ||||
Sequence: K | ||||||
Modified residue | 404 | N6-acetyllysine | ||||
Sequence: K | ||||||
Modified residue | 519 | Phosphoserine | ||||
Sequence: S | ||||||
Modified residue | 550 | N6-acetyllysine; alternate | ||||
Sequence: K | ||||||
Cross-link | 550 | Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO2); alternate | ||||
Sequence: K | ||||||
Modified residue | 639 | Phosphoserine; by CDK1 | ||||
Sequence: S | ||||||
Modified residue | 649 | Phosphoserine | ||||
Sequence: S | ||||||
Modified residue | 656 | Phosphoserine | ||||
Sequence: S | ||||||
Cross-link | 664 | Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO2) | ||||
Sequence: K | ||||||
Modified residue | 759 | Phosphoserine | ||||
Sequence: S |
Post-translational modification
Phosphorylation at Ser-303 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 (By similarity).
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.
Keywords
- PTM
Proteomic databases
2D gel databases
PTM databases
Expression
Tissue specificity
Expressed in thymus, testis, spleen and lung. Within testis, expressed in almost all cells except elongated spermatids.
Induction
Up-regulated in proliferating cells, and down-regulated in quiescent or differentiated cells. Early induced by E1A in postmitotic cells. Down-regulated by aphidicolin.
Gene expression databases
Interaction
Subunit
Interacts with DNMT3A and DNMT3B. Interacts with DNMT1; the interaction is direct. Interacts with USP7; leading to its deubiquitination. Interacts with HDAC1, but not with HDAC2. Interacts with BLTP3A. Interacts with PML. Interacts with EHMT2. Binds hemimethylated CpG containing oligonucleotides (PubMed:15361834, PubMed:17994007, PubMed:18772888, PubMed:18772891, PubMed:19056828, PubMed:19798101, PubMed:21268065).
Interacts with PRAMEL7 (PubMed:28604677).
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 (By similarity).
Interacts with UHRF2 (By similarity).
Interacts with FANCD2 (By similarity).
Interacts with TET1 isoform 2; this interaction induces the recruitment of TET1 isoform 2 to replicating heterochromatin (PubMed:36056023).
Interacts with PRAMEL7 (PubMed:28604677).
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 (By similarity).
Interacts with UHRF2 (By similarity).
Interacts with FANCD2 (By similarity).
Interacts with TET1 isoform 2; this interaction induces the recruitment of TET1 isoform 2 to replicating heterochromatin (PubMed:36056023).
Protein-protein interaction databases
Miscellaneous
Structure
Family & Domains
Features
Showing features for domain, region, compositional bias, zinc finger.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Domain | 1-78 | Ubiquitin-like | ||||
Sequence: MWIQVRTMDGKETHTVNSLSRLTKVQELRKKIEEVFHVEPQLQRLFYRGKQMEDGHTLFDYDVRLNDTIQLLVRQSLA | ||||||
Region | 83-119 | Disordered | ||||
Sequence: TKERDSELSDSDSGYGVGHSESDKSSTHGEGAAEADD | ||||||
Compositional bias | 105-119 | Basic and acidic residues | ||||
Sequence: DKSSTHGEGAAEADD | ||||||
Region | 129-205 | Tudor-like 1 | ||||
Sequence: GLYKVNEYVDVRDNIFGAWFEAQVVQVQKRALSEDEPCSSSAVKTSEDDIMYHVKYDDYPEHGVDIVKAKNVRARAR | ||||||
Region | 212-280 | Tudor-like 2 | ||||
Sequence: NLEVGQVVMANYNVDYPRKRGFWYDVEICRKRQTRTARELYGNIRLLNDSQLNNCRIMFVDEVLMIELP | ||||||
Region | 293-306 | Linker | ||||
Sequence: PPPALRNTGKSGPS | ||||||
Zinc finger | 304-371 | PHD-type | ||||
Sequence: GPSCRFCKDDENKPCRKCACHVCGGREAPEKQLLCDECDMAFHLYCLKPPLTSVPPEPEWYCPSCRTD | ||||||
Region | 338-342 | Histone H3R2me0 binding | ||||
Sequence: CDECD | ||||||
Region | 358-360 | Histone H3R2me0 binding | ||||
Sequence: PPE | ||||||
Domain | 424-586 | YDG | ||||
Sequence: GPIPGVPVGTMWRFRVQVSESGVHRPHVAGIHGRSNDGAYSLVLAGGYEDDVDNGNYFTYTGSGGRDLSGNKRTAGQSSDQKLTNNNRALALNCHSPINEKGAEAEDWRQGKPVRVVRNMKGGKHSKYAPAEGNRYDGIYKVVKYWPERGKSGFLVWRYLLRR | ||||||
Region | 450-451 | Required to promote base flipping | ||||
Sequence: HV | ||||||
Region | 471-474 | Required for formation of a 5-methylcytosine-binding pocket | ||||
Sequence: YEDD | ||||||
Region | 483-486 | Required for formation of a 5-methylcytosine-binding pocket | ||||
Sequence: YTGS | ||||||
Region | 623-666 | Disordered | ||||
Sequence: EKSRKRPAKALEQGPSSSKTGKSKQKSTGPTLSSPRASKKSKLE | ||||||
Compositional bias | 635-666 | Polar residues | ||||
Sequence: QGPSSSKTGKSKQKSTGPTLSSPRASKKSKLE | ||||||
Zinc finger | 713-752 | RING-type | ||||
Sequence: CICCQELVFRPVTTVCQHNVCKDCLDRSFRAQVFSCPACR |
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).
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 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) (PubMed:17994007).
The YDG domain 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:18772888).
The YDG domain also recognizes and binds 5-hydroxymethylcytosine (5hmC)
The YDG domain 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:18772888).
The YDG domain also recognizes and binds 5-hydroxymethylcytosine (5hmC)
The RING finger is required for ubiquitin ligase activity.
Keywords
- Domain
Phylogenomic databases
Family and domain databases
Sequence & Isoform
- Sequence statusComplete
This entry describes 2 isoforms produced by Alternative splicing.
Q8VDF2-1
This isoform has been chosen as the canonical sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.
- Name1
- Length782
- Mass (Da)88,304
- Last updated2005-06-07 v2
- ChecksumDC5EEDFCDF69619B
Q8VDF2-2
- Name2
- Differences from canonical
- 293-301: PPPALRNTG → R
Computationally mapped potential isoform sequences
There is 1 potential isoform mapped to this entry
Entry | Entry name | Gene name | Length | ||
---|---|---|---|---|---|
E9Q5Y5 | E9Q5Y5_MOUSE | Uhrf1 | 146 |
Features
Showing features for sequence conflict, compositional bias, alternative sequence.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Sequence conflict | 104 | in Ref. 3; BAE30624 | ||||
Sequence: S → P | ||||||
Compositional bias | 105-119 | Basic and acidic residues | ||||
Sequence: DKSSTHGEGAAEADD | ||||||
Sequence conflict | 118 | in Ref. 3; BAE31708/BAE31605/BAE30730/BAE29605 | ||||
Sequence: D → G | ||||||
Sequence conflict | 214 | in Ref. 6; BAB79496 | ||||
Sequence: E → K | ||||||
Alternative sequence | VSP_044395 | 293-301 | in isoform 2 | |||
Sequence: PPPALRNTG → R | ||||||
Sequence conflict | 449 | in Ref. 6; BAB79496 | ||||
Sequence: P → L | ||||||
Sequence conflict | 455-456 | in Ref. 6; BAB79496 | ||||
Sequence: HG → PW | ||||||
Sequence conflict | 471 | in Ref. 3; BAE27560 | ||||
Sequence: Y → H | ||||||
Compositional bias | 635-666 | Polar residues | ||||
Sequence: QGPSSSKTGKSKQKSTGPTLSSPRASKKSKLE | ||||||
Sequence conflict | 637 | in Ref. 3; BAE26398 | ||||
Sequence: P → A | ||||||
Sequence conflict | 702 | in Ref. 3; BAE31708/BAE31605/BAE30730/BAE29605 | ||||
Sequence: I → V | ||||||
Sequence conflict | 753 | in Ref. 5; AAH22167 | ||||
Sequence: F → Y |
Keywords
- Coding sequence diversity
- Technical term
Sequence databases
Nucleotide Sequence | Protein Sequence | Molecule Type | Status | |
---|---|---|---|---|
D87908 EMBL· GenBank· DDBJ | BAA74579.1 EMBL· GenBank· DDBJ | mRNA | ||
AF274046 EMBL· GenBank· DDBJ | AAK55743.1 EMBL· GenBank· DDBJ | mRNA | ||
AK075819 EMBL· GenBank· DDBJ | BAC35985.1 EMBL· GenBank· DDBJ | mRNA | ||
AK143688 EMBL· GenBank· DDBJ | BAE25499.1 EMBL· GenBank· DDBJ | mRNA | ||
AK145376 EMBL· GenBank· DDBJ | BAE26398.1 EMBL· GenBank· DDBJ | mRNA | ||
AK145543 EMBL· GenBank· DDBJ | BAE26496.1 EMBL· GenBank· DDBJ | mRNA | ||
AK146951 EMBL· GenBank· DDBJ | BAE27560.1 EMBL· GenBank· DDBJ | mRNA | ||
AK147046 EMBL· GenBank· DDBJ | BAE27632.1 EMBL· GenBank· DDBJ | mRNA | ||
AK150489 EMBL· GenBank· DDBJ | BAE29605.1 EMBL· GenBank· DDBJ | mRNA | ||
AK151701 EMBL· GenBank· DDBJ | BAE30624.1 EMBL· GenBank· DDBJ | mRNA | ||
AK151837 EMBL· GenBank· DDBJ | BAE30730.1 EMBL· GenBank· DDBJ | mRNA | ||
AK152930 EMBL· GenBank· DDBJ | BAE31605.1 EMBL· GenBank· DDBJ | mRNA | ||
AK153083 EMBL· GenBank· DDBJ | BAE31708.1 EMBL· GenBank· DDBJ | mRNA | ||
AC026385 EMBL· GenBank· DDBJ | - | Genomic DNA | No translation available. | |
BC022167 EMBL· GenBank· DDBJ | AAH22167.1 EMBL· GenBank· DDBJ | mRNA | ||
AB066246 EMBL· GenBank· DDBJ | BAB79496.1 EMBL· GenBank· DDBJ | Genomic DNA |