UHRF proteins as epigenetic integrators coordinating DNA methylation, histone modifications, and chromatin remodeling

UHRF1 and UHRF2 are multidomain epigenetic regulators that are paralogous in structure but slightly different in function. UHRF1 main function is to participate in replication coupled maintenance DNA methylation. UHRF1 recognizes hemi-methylated DNA and specific histone states, and it recruits and activates DNMT1 to newly replicated chromatin. This function is a key mechanism for faithful DNA methylation transmission and maintenance of cellular identity. In various cancers, abnormal UHRF1 activity has been linked to abnormal chromatin regulation, genome instability, tumour progression, and resistance to therapy. UHRF2 preferentially binds 5-hydroxymethylcytosine (5hmC), a cytosine modification that is particularly enriched in brain tissue and in differentiated post-mitotic cells. Through this recognition, UHRF2 engages chromatin and DNA repair factors, including XRCC1, linking 5hmC to both chromatin regulation and repair at hydroxymethylated sites. While the UHRF2-5hmC-XRCC1 axis is supported by direct biochemical evidence, its broader roles in neuronal regulation, memory, and development mainly on genetic models and context-dependent observations. Both proteins undergo post-translational modifications, including phosphorylation, ubiquitination, acetylation, and SUMOylation, which affect protein stability, localization, chromatin binding, and molecular activity. This review examines the domain architecture, DNA and histone recognition mechanisms, cell cycle regulation, genome maintenance functions, disease associations, and therapeutic relevance of UHRF1 and UHRF2. It focuses on the difference between UHRF1 associated epigenetic inheritance and UHRF2 associated hydroxymethylation dependent chromatin plasticity. The review also addresses novel therapeutic approaches such as domain selective inhibition, targeted protein degradation, and distinguishes preclinical results from clinically validated findings. These similarities and differences between the paralogs could help design more selective and biologically relevant epigenetic treatments.