Ubiquitin-like with PHD and ring finger domains 1 (UHRF1)

Ubiquitin-like with PHD and ring finger domains 1 (UHRF1) is a multi-domain epigenetic integrator that plays a pivotal role in maintaining DNA methylation patterns during DNA replication. It functions by recognizing hemi-methylated DNA through its SRA domain and methylated histone H3K9 through its TTD and PHD domains, subsequently recruiting DNA methyltransferase 1 (DNMT1) to the replication fork (UniProt Q96T88). UHRF1 also possesses E3 ubiquitin ligase activity via its RING domain, which targets histone H3 for ubiquitination, further facilitating DNMT1 recruitment (PubMed: 23152191). In many human cancers, UHRF1 is significantly overexpressed, leading to the silencing of tumor suppressor genes and promoting oncogenic transformation and metastasis (PubMed: 28655773). As a result, UHRF1 is an attractive therapeutic target; small molecule inhibitors and PROTACs are being developed to disrupt its chromatin binding or induce its degradation to restore normal epigenetic landscapes in malignant cells (PubMed: 31110353). This protein's ability to link DNA methylation and histone modification makes it a central node in epigenetic regulation.

Other names

Np95ICBP90RNF106Nuclear protein 95Inverted CCAAT box-binding protein of 90 kDaNuclear zinc finger protein Np95

Inhibition of UHRF1 domains (TTD, PHD, or SRA) to disrupt recruitment of DNMT1 and prevent maintenance of DNA methylation, or induction of UHRF1 protein degradation via PROTAC technology.