UHRF1
Description
The UHRF1 (ubiquitin like with PHD and ring finger domains 1) is a protein-coding gene located on chromosome 19.
Ubiquitin-like, containing PHD and RING finger domains, 1, also known as UHRF1, is a protein which in humans is encoded by the UHRF1 gene.
== Function == This gene encodes a member of a subfamily of RING-finger type E3 ubiquitin ligases. The protein binds to hemi-methylated DNA during S-phase and recruits the main DNA methyltransferase protein, DNMT1, to regulate chromatin structure and 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, and functions in the p53-dependent DNA damage checkpoint. Multiple transcript variants encoding different isoforms have been found for this gene. It was originally identified as a direct regulator of topoisomerase 2a, but this has subsequently been disproven. Uhrf1 has been extensively studied in vivo using zebrafish.
== Clinical significance == UHRF1 has recently been identified as a novel oncogene in hepatocellular carcinoma, the primary type of liver cancer.
UHRF1 is a multidomain protein that acts as a key epigenetic regulator by linking DNA methylation and chromatin modification. It binds to hemimethylated DNA at replication forks through its YDG domain and recruits DNMT1 methyltransferase to ensure faithful propagation of DNA methylation patterns during DNA replication. Beyond its role in maintaining DNA methylation, UHRF1 plays a crucial role in chromatin modification. Its tudor-like regions and PHD-type zinc fingers recognize and bind histone H3 trimethylated at Lys-9 (H3K9me3) and unmethylated at Arg-2 (H3R2me0), respectively, recruiting chromatin proteins. It is concentrated in pericentric heterochromatin, where it recruits different chromatin modifiers required for chromatin replication. UHRF1 also localizes to euchromatic regions, where it negatively regulates transcription by influencing DNA methylation and histone modifications. UHRF1 possesses E3 ubiquitin-protein ligase activity, mediating the ubiquitination of target proteins such as histone H3 and PML. However, the relationship between its E3 ubiquitin-protein ligase activity and its role in chromatin in vivo remains unclear. UHRF1 participates in DNA repair by cooperating with UHRF2 to ensure the recruitment of FANCD2 to interstrand cross-links (ICLs), leading to FANCD2 activation. It is also essential for proper spindle architecture, catalyzing Lys-63-linked ubiquitination of KIF11, thereby controlling KIF11 localization on the spindle. {ECO:0000269|PubMed:10646863, ECO:0000269|PubMed:15009091, ECO:0000269|PubMed:15361834, ECO:0000269|PubMed:17673620, ECO:0000269|PubMed:17967883, ECO:0000269|PubMed:19056828, ECO:0000269|PubMed:21745816, ECO:0000269|PubMed:21777816, ECO:0000269|PubMed:22945642, ECO:0000269|PubMed:30335751, ECO:0000269|PubMed:37728657}
UHRF1 is also known as ICBP90, Np95, RNF106, TDRD22, hNP95, hUHRF1, huNp95.
