Ubiquitin-like with PHD and RING finger domains 1 (UHRF1) Set-and-RING-associated (SRA) domain (UHRF1 SRA domain)

Ubiquitin-like with PHD and RING finger domains 1 (UHRF1) is a multi-domain protein that plays a critical role in maintaining DNA methylation patterns during cell division (UniProt Q96T88). The Set-and-RING-associated (SRA) domain is a specialized reader module that specifically recognizes hemi-methylated DNA at the replication fork (Arita et al., Nature 2008). By binding to these sites, the SRA domain recruits DNA methyltransferase 1 (DNMT1) to ensure the faithful inheritance of epigenetic marks onto the newly synthesized DNA strand (UniProt Q96T88). UHRF1 is frequently overexpressed in various cancers, where it contributes to the silencing of tumor suppressor genes and promotes uncontrolled cell proliferation (Ashraf et al., Mol Cancer 2017). Consequently, the SRA domain has emerged as a high-priority therapeutic target for the development of epigenetic inhibitors (Myrianthopoulos et al., J Med Chem 2016). Small molecule inhibitors targeting the SRA domain aim to disrupt the UHRF1-DNMT1 axis, leading to the reactivation of silenced genes and induction of apoptosis in malignant cells (Ashraf et al., Mol Cancer 2017). While several experimental compounds have shown promise in preclinical models, achieving high selectivity and managing the risks of global hypomethylation remain significant challenges in drug development. Future therapies may focus on combining SRA inhibitors with other epigenetic modulators to enhance efficacy and reduce toxicity.

Other names

Np95ICBP90RNF106Set-and-RING-associated domain of UHRF1Ubiquitin-like-containing PHD and RING finger domains 1

The mechanism of action for drugs targeting the UHRF1 SRA domain involves the competitive or allosteric inhibition of its binding to hemi-methylated CpG sites, which prevents the recruitment of DNA methyltransferase 1 (DNMT1) and results in the loss of DNA methylation maintenance (Myrianthopoulos et al., J Med Chem 2016; Arita et al., Nature 2008).