UHRF1

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]

Ubiquitin Like With PHD And Ring Finger Domains 1

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 UHRF1 to ensure recruitment of FANCD2 to interstrand cross-links (ICLs) leading to FANCD2 activation.

Biological Process cell cycle Source:UniProtKB-KW
Biological Process chromatin organization Source:UniProtKB-KW
Biological Process DNA repair Source:UniProtKB-KW
Biological Process histone monoubiquitination Source:BHF-UCL
Biological Process histone ubiquitination Source:UniProtKB1 Publication
Biological Process maintenance of DNA methylation Source:UniProtKB1 Publication
Biological Process negative regulation of transcription by RNA polymerase II Source:UniProtKB1 Publication
Biological Process positive regulation of DNA topoisomerase (ATP-hydrolyzing) activity Source:BHF-UCL1 Publication
Biological Process positive regulation of protein metabolic process Source:BHF-UCL1 Publication
Biological Process positive regulation of transcription by RNA polymerase II Source:BHF-UCL1 Publication
Biological Process protein autoubiquitination Source:UniProtKB2 Publications
Biological Process protein ubiquitination Source:GO_Central1 Publication
Biological Process regulation of epithelial cell proliferation Source:BHF-UCL1 Publication
Biological Process ubiquitin-dependent protein catabolic process Source:UniProtKB1 Publication

Nucleus
Localizes to replication foci. Enriched in pericentric heterochromatin. Also localizes to euchromatic regions.

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

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.
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.