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Article Abstract
Histone H2A monoubiquitination at lysine 119 (H2AK119ub1) is a central epigenetic regulator that governs transcriptional control, chromatin architecture remodeling, and lineage commitment. The precise homeostatic balance of H2AK119ub1 is maintained through antagonistic coordination between polycomb repressive complex 1 and specialized deubiquitinases, forming a precise equilibrium that is critical for the regulation of gene expression. Dysregulation of H2AK119ub1 has been mechanistically linked to multiple human pathologies, indicating that its regulatory axis is a promising therapeutic target. This review provides a comprehensive analysis of the molecular mechanisms underlying H2AK119ub1 deposition/removal, its causal relationships with disease progression, and current pharmacological strategies targeting this pathway. This study offers novel perspectives on H2AK119ub1-mediated epigenetic regulation and proposes a framework for developing targeted therapeutic interventions.
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| http://dx.doi.org/10.1016/j.bcp.2025.117122 | DOI Listing |
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Article Synopsis
- H3K27me3 is a repressive histone modification linked to facultative heterochromatin, established by PRC2 and removed by KDM6 family demethylases.
- Cryo-EM studies reveal how KDM6B interacts with nucleosomal and extranucleosomal DNA to effectively demethylate H3K27, a step essential for reactivating silenced chromatin.
- Additional findings suggest that linker histones and H2AK119ub1 inhibit KDM6B activity, indicating their removal is necessary for successful H3K27 demethylation and activation of heterochromatin.