Mono-ubiquitination of histone H2A at lysine 119 (H2AK119Ub) is a prominent post‑translational modification deposited by the Polycomb repressive complex 1 (PRC1), affecting roughly 10% of all H2A molecules in mammals. This versatile histone mark plays a critical role in organizing the genome into functional domains, orchestrating gene silencing, and maintaining cell identities during development. A dynamic balance between “writer” enzymes (mainly PRC1) and “eraser” deubiquitinases (DUBs) such as BAP1 and USP16 ensures tight regulation of H2AK119Ub deposition and removal. Moreover, H2AK119Ub acts as a recruitment signal for specific “reader” proteins, which then elicit downstream effects—modulating transcription, safeguarding genome integrity, and shaping cellular identity. Disruption of this signaling network is increasingly recognized as a driver of human diseases, particularly cancer, positioning H2AK119Ub as a central hub in epigenetic regulation and a promising therapeutic target.

Systematic dissection of the molecular machineries that govern H2AK119Ub focuses on how distinct “reader” proteins interpret this mark to elicit diverse biological outcomes. One key reader is JARID2, a non‑catalytic component of the PRC2.2 complex. Despite lacking intrinsic demethylase activity, JARID2 harbors an N‑terminal ubiquitin‑interacting motif (UIM) that binds H2AK119Ub with high specificity. Structural studies using cryo‑electron microscopy reveal that JARID2 coordinates with another PRC2.2 subunit, AEBP2, to form a multivalent interface that anchors PRC2 onto H2AK119Ub‑marked nucleosomes, thereby promoting the deposition of H3K27me3, a hallmark of facultative heterochromatin. This mechanism is crucial for X‑chromosome inactivation and for maintaining developmental gene silencing. Notably, JARID2 overexpression in lung, colon, and breast cancer correlates with enhanced PRC2 activity and suppression of tumor suppressors, whereas its loss in myeloid neoplasms impairs PRC2 recruitment and drives leukemogenesis. Thus, JARID2 functions as a molecular rheostat whose context‑dependent misregulation can either promote or suppress tumorigenesis.

Another major reader, DNMT3A1, connects Polycomb repression to de novo DNA methylation. Unlike its shorter isoform DNMT3A2, DNMT3A1 possesses a unique N‑terminal ubiquitin‑dependent recruitment (UDR) region that binds H2AK119Ub‑modified nucleosomes with high affinity. Structural analysis identifies a multivalent binding mode in which the UDR engages both the H2A–H2B acidic patch and the ubiquitin moiety, while avoiding steric clashes with other chromatin interfaces. Under normal conditions, DNMT3A1 is targeted to Polycomb‑repressed regions via the UDR–H2AK119Ub interaction but remains catalytically latent, with its methylation activity requiring additional activation signals such as the recognition of H3K36me2/3 by its PWWP domain. This “positioning without firing” model explains why H2AK119Ub‑marked loci typically remain hypomethylated in physiology. However, in cancer‑associated mutants where the PWWP domain loses its ability to sense H3K36me2/3, the UDR‑driven recruitment causes DNMT3A1 to be aberrantly targeted to H2AK119Ub‑enriched facultative heterochromatin, leading to DNA hypermethylation at Polycomb target genes—a feature frequently observed in numerous cancers and developmental syndromes. These mechanistic insights open avenues for therapeutic strategies to block UDR‑mediated recruitment and restore proper DNA methylation patterns.

RYBP, a defining component of variant PRC1 (vPRC1), serves as both a reader and amplifier of H2AK119Ub signaling. Through its NZF domain, RYBP recognizes H2AK119Ub and stabilizes vPRC1 on chromatin independent of H3K27me3, enabling de novo establishment and spreading of Polycomb domains. In a feedforward loop, RYBP‑bound vPRC1 not only interprets H2AK119Ub but also catalyzes its deposition on neighboring nucleosomes, thereby reinforcing and propagating the repressive chromatin state. This amplification mechanism is essential for maintaining silencing of the inactive X chromosome and for the robust repression of developmental genes. Recent cryo‑EM studies have further elucidated a “read‑write” mechanism whereby the RYBP–PRC1 complex engages nucleosomes in two modes—one ubiquitin‑independent and the other specifically recognizing H2AK119Ub—to coordinate the propagation of Polycomb repression. Dysregulation of RYBP has been implicated in various cancers; loss of RYBP correlates with enhanced tumor growth and poor prognosis, underscoring its tumor‑suppressive functions in many contexts.

Beyond these three paradigmatic readers, additional H2AK119Ub‑binding proteins, including SSX and RSF1, also play important roles. The SS18::SSX fusion oncoprotein, generated by a chromosomal translocation specific to synovial sarcoma, retargets the BAF chromatin remodeling complex to H2AK119Ub‑marked loci, disrupting the balance between Polycomb and BAF activities and driving aberrant transcription. RSF1, which binds H2AK119Ub through a ubiquitin‑associated (UAB) domain, facilitates displacement of PRC1 from chromatin and promotes transcriptional activation at selected loci. RSF1 amplification in ovarian and breast cancers contributes to genomic instability, highlighting the dual faces of H2AK119Ub as a mark that can both repress and activate gene expression depending on the reader protein engaged.

Dysregulation of H2AK119Ub signaling is increasingly recognized as a driver of human diseases. Germline mutations in BAP1, for example, define a cancer predisposition syndrome associated with uveal melanoma and mesothelioma. Overexpression of the deubiquitinase USP16 in a Down syndrome mouse model leads to reduced hematopoietic stem cell self‑renewal and impaired neural progenitor expansion due to aberrant erasure of H2AK119Ub, whereas USP16 deletion causes accumulation of this mark and defective hematopoietic lineage commitment. Collectively, these findings establish H2AK119Ub as a critical epigenetic regulator whose dysregulation contributes to malignant transformation, developmental disorders, and other pathological conditions. By integrating structural biology, biochemistry, and disease models, a comprehensive framework emerges for understanding how this single histone mark is interpreted by multiple readers to elicit diverse biological outcomes, and highlights the therapeutic potential of targeting these recognition events in diseases marked by epigenetic misregulation.
DOI
10.1007/s11684-026-1209-z