UniProt ID: E7EZF3
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. However, it is still unclear how E3 ubiquitin-protein ligase activity is related to its role in chromatin in vivo (By similarity). Required for pregastrula and lens development. {ECO:0000250, ECO:0000269|PubMed:21126517}.
CATALYTIC ACTIVITY: Reaction=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.; EC=2.3.2.27;
PATHWAY: Protein modification; protein ubiquitination.
SUBCELLULAR LOCATION: Nucleus {ECO:0000255|PROSITE- ProRule:PRU00358}. Cytoplasm {ECO:0000269|PubMed:22072796}. Note=Localizes to replication foci. Enriched in pericentric heterochromatin. Also localizes to euchromatic regions (By similarity). {ECO:0000250}.
TISSUE SPECIFICITY: Expressed in proliferating tissues. Highly expressed 24-48 hours after fertilization (hpf) in rapidly proliferating tissues, including the tectum, retina and brachial arches. Preferentially expressed in the liver bud and expression is maintained in the fully developed liver. Also expressed in the proximal gut. In adult, the highest expression is detected in testis. {ECO:0000269|PubMed:17242348}.
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). {ECO:0000250}.
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). {ECO:0000250}.
DOMAIN: The RING finger is required for ubiquitin ligase activity. {ECO:0000250}.
PTM: Phosphorylation at Ser-649 is required for gastrulation. {ECO:0000269|PubMed:22072796}.
DISRUPTION PHENOTYPE: Embryos have a small head, eyes, jaw and an underdeveloped gut. Moreover many mutants display diminished yolk consumption and uninflated swim bladder as well as embryonic lethality. DNA methylation is impaired during embryogenesis and embryos display defects in lens development and maintenance. No fertility defects are noted for heterozygous animals. {ECO:0000269|PubMed:17242348, ECO:0000269|PubMed:21126517}.
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