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Details on Person UniProt:Q96T88 UHRF1

Class:Id	ReferenceGeneProduct:357157
_chainChangeLog	chain:1-793 added on Fri February 6 2015
_displayName	UniProt:Q96T88 UHRF1
_timestamp	2026-02-20 21:45:47
chain	chain:1-793
checksum	E65B15657525C89F
comment	FUNCTION E3 ubiquitin-protein ligase that acts as a key epigenetic regulator by bridging DNA methylation and chromatin modification (PubMed:10646863, PubMed:15009091, PubMed:19056828, PubMed:23022729, PubMed:24013172, PubMed:27595565, PubMed:30104358, PubMed:30392929, PubMed:30392931, PubMed:39607687). 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 (PubMed:23022729, PubMed:24013172, PubMed:27595565, PubMed:30104358, PubMed:30392929, PubMed:30392931, PubMed:39607687). 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 (PubMed:15361834, PubMed:17673620, PubMed:17967883, PubMed:18772889, PubMed:21745816, PubMed:21777816, PubMed:22100450, PubMed:22837395, PubMed:23022729, PubMed:27595565, PubMed:30104358). UHRF1 then mediates histone H3 'Lys-18' monoubiquitination (H3K18ub), a docking site for DNMT1, leading to DNMT1 recruitment and replication-coupled DNA methylation maintenance (PubMed:27595565). Also mediates histone H3 'Lys-14' and 'Lys-23' ubiquitination (H3K14ub and H3K23ub) at lower level (PubMed:24013172, PubMed:27595565). Histone ubiquitin ligase activity also stimulates the methyltransferase activity of SUV39H1 and/or SUV39H2, promoting accumulation of H3K9me3 histone mark to reinformce heterochromatin state (PubMed:39631394). 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 (PubMed:21777816). Plays a role in DNA repair by cooperating with UHRF2 to ensure recruitment of FANCD2 to interstrand cross-links (ICLs) leading to FANCD2 activation (PubMed:30335751). Also ubiquitinates non-histone proteins, such as histone H3, KIF11 and PML (PubMed:22945642, PubMed:37728657). 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 (PubMed:37728657).CATALYTIC ACTIVITY S-ubiquitinyl-[E2 ubiquitin-conjugating enzyme]-L-cysteine + [acceptor protein]-L-lysine = [E2 ubiquitin-conjugating enzyme]-L-cysteine + N(6)-ubiquitinyl-[acceptor protein]-L-lysine.PATHWAY Protein modification; protein ubiquitination.SUBUNIT Interacts with DNMT1; the interaction is direct (PubMed:17673620, PubMed:21745816). Interacts with DNMT3A and DNMT3B (By similarity). Interacts with HDAC1, but not with HDAC2 (PubMed:15361834). Interacts with BLTP3A (PubMed:15361834). Interacts with EHMT2 (PubMed:19056828). 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 (PubMed:32051553). Interacts with UHRF2 (PubMed:30335751). Interacts with FANCD2 (PubMed:30335751). Interacts with TET1 isoform 2; this interaction induces the recruitment of TET1 isoform 2 to replicating heterochromatin (By similarity).INTERACTION Associated with replicating DNA from early to late S phase, including at replicating pericentric heterochromatin (PubMed:17673620). Also localizes to euchromatic regions (PubMed:21777816). In non-S-phase cells, homogenously distributed through the nucleus (By similarity).ALTERNATIVE PRODUCTS 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 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.DOMAIN 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) (PubMed:21489993, PubMed:21777816, PubMed:22100450). 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, 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).PTM Phosphorylation at Ser-298 of the linker region by PKA decreases the binding to H3K9me3 (PubMed:15178447, PubMed:22837395). Phosphorylation at Ser-639 by CDK1 during M phase impairs interaction with USP7, preventing deubiquitination and leading to degradation by the proteasome (PubMed:22411829).PTM Ubiquitinated; which leads to proteasomal degradation (PubMed:15009091). Autoubiquitinated; interaction with USP7 leads to deubiquitination and prevents degradation (PubMed:17967883, PubMed:21745816, PubMed:22411829). Ubiquitination and degradation takes place during M phase, when phosphorylation at Ser-639 prevents interaction with USP7 and subsequent deubiquitination (PubMed:22411829). Polyubiquitination may be stimulated by DNA damage (PubMed:15009091).DISEASE 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.SEQUENCE CAUTION Truncated N-terminus.
created	[InstanceEdit:354386] Schmidt, EE, 2008-06-18 04:45:12
description	recommendedName: E3 ubiquitin-protein ligase UHRF1 ecNumber evidence="33 36 39 40 42"2.3.2.27 alternativeName: fullName evidence="50"Inverted CCAAT box-binding protein of 90 kDa alternativeName: fullName evidence="48"Nuclear zinc finger protein Np95 shortName evidence="48"HuNp95 shortName evidence="48"Nuclear protein 95 shortName evidence="48"hNp95 alternativeName: RING finger protein 106 alternativeName: fullName evidence="50"Transcription factor ICBP90 alternativeName: fullName evidence="49"Ubiquitin-like PHD and RING finger domain-containing protein 1 shortName evidence="49"hUHRF1
geneName	UHRF1 ICBP90 NP95 RNF106
identifier	Q96T88
isSequenceChanged	FALSE
keyword	3D-structure Acetylation Alternative splicing Cell cycle Chromatin regulator Chromosome DNA damage DNA repair DNA-binding Isopeptide bond Metal-binding Nucleus Phosphoprotein Proteomics identification Reference proteome Repeat Repressor Transcription Transcription regulation Transferase Ubl conjugation Ubl conjugation pathway Zinc Zinc-finger
modified	[InstanceEdit:9836292] Weiser, Joel, 2023-05-25 [InstanceEdit:9852000] Weiser, Joel, 2023-11-03 [InstanceEdit:9862192] Weiser, Joel, 2024-02-26 [InstanceEdit:9926675] Weiser, Joel, 2024-11-03 [InstanceEdit:9983091] Weiser, Joel, 2026-02-20
name	UHRF1
referenceDatabase	[ReferenceDatabase:2] UniProt
referenceGene	[ReferenceDNASequence:9001525] ENSEMBL:ENSG00000276043 UHRF1 [Homo sapiens]
secondaryIdentifier	UHRF1_HUMAN A0JBR2 A8K024 B2RBA9 Q2HIX7 Q8J022 Q9H6S6 Q9P115 Q9P1U7
sequenceLength	793
species	[Species:48887] Homo sapiens
(isoformParent)	[ReferenceIsoform:8966353] UniProt:Q96T88-1 UHRF1 [Homo sapiens] [ReferenceIsoform:8966354] UniProt:Q96T88-2 UHRF1 [Homo sapiens]
(referenceEntity)	[EntityWithAccessionedSequence:212103] UHRF1 [nucleoplasm] [Homo sapiens] [EntityWithAccessionedSequence:9818452] UHRF1 [cytosol] [Homo sapiens]
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No pathways have been reviewed or authored by UniProt:Q96T88 UHRF1 (357157)