E3 ubiquitin-protein ligase UHRF1 (UHRF1)

E3 ubiquitin-protein ligase UHRF1 is a multidomain nuclear protein acting as a master regulator of epigenetic inheritance, primarily through maintenance of DNA methylation during cell division. UHRF1 recognizes hemi-methylated CpG DNA via its SRA domain and recruits maintenance DNA methyltransferase DNMT1 to newly replicated DNA, ensuring faithful propagation of methylation patterns. Structurally, UHRF1 comprises five key domains: a ubiquitin-like (UBL) domain, tandem Tudor (TTD) domain, plant homeodomain (PHD) finger, SET and RING-associated (SRA) domain, and a RING finger domain that provides E3 ubiquitin ligase activity. It interacts with histone marks and other chromatin-modifying proteins, such as HDAC1 and SUV39H1, forming the core of a complex termed the epigenetic code replication machinery (ECReM), essential for synchronizing chromatin state with DNA replication. UHRF1 is overexpressed in numerous human cancers, functioning as an oncogene by silencing tumor suppressor genes through epigenetic mechanisms. As such, it is both a validated biomarker and an emerging therapeutic target, especially in epigenetic cancer therapy, though clinical inhibitors are not yet in standard use.

Other names

ICBP90NP95RNF106HuNp95hNp95hUHRF1FLJ21925TDRD22inverted CCAAT box-binding protein of 90 kDanuclear protein 95nuclear zinc finger protein Np95RING finger protein 106RING-type E3 ubiquitin transferase UHRF1transcription factor ICBP90ubiquitin-like PHD and RING finger domain-containing protein 1Ubiquitin-like-containing PHD and RING finger domains protein 1nuclear phosphoprotein 95

Putative inhibitors would block UHRF1 recruitment to hemimethylated DNA or disrupt its interaction with DNMT1, leading to DNA hypomethylation and reactivation of silenced tumor suppressor genes