- RING1A and RING1B are closely related E3 ubiquitin ligases that function as central catalytic components of Polycomb Repressive Complex 1 (PRC1). Together, they establish one of the best-characterized molecular signatures of Polycomb-mediated chromatin regulation: monoubiquitination of histone H2A at lysine 119, known as H2AK119ub or H2AK119ub1. Through this activity, RING1A and RING1B contribute to transcriptional repression, chromatin organization, developmental gene regulation, stem-cell biology, cellular identity, and epigenetic memory.
- RING1A and RING1B belong to the RING finger protein family and contain a RING domain that is essential for their ubiquitin ligase activity. Although both proteins can function as catalytic components of PRC1, RING1B is generally considered the predominant RING1 protein in many mammalian cellular contexts. RING1A can partially compensate for loss of RING1B in some settings, illustrating both functional overlap and biological differences between the two proteins.
- The principal enzymatic activity of RING1A and RING1B is the transfer of ubiquitin to histone H2A. Within PRC1, these proteins catalyze monoubiquitination of lysine 119 on histone H2A, producing H2AK119ub. This modification occurs primarily on nucleosomal histone H2A and is strongly associated with Polycomb-repressed chromatin. H2AK119ub is therefore an important molecular connection between PRC1 enzymatic activity and the regulation of gene expression.
- RING1A and RING1B do not normally function as isolated ubiquitin ligases. Their activity is strongly influenced by interactions with other PRC1 proteins, particularly PCGF proteins, which are also known as Polycomb group RING finger proteins. A RING1 protein and a PCGF protein form an important catalytic module within PRC1, with the PCGF component contributing to the organization and regulation of the ubiquitin ligase complex. Different PCGF proteins are incorporated into distinct PRC1 complexes, contributing to the molecular diversity of the PRC1 family.
- PRC1 is not a single uniform complex. Instead, mammalian cells contain multiple PRC1 assemblies with different combinations of catalytic and accessory proteins. Canonical PRC1 complexes commonly contain RING1A or RING1B, a PCGF protein, a chromobox protein such as CBX2, CBX4, CBX6, CBX7, or CBX8, and a Polyhomeotic protein. These complexes can recognize H3K27me3 through CBX chromodomains, providing an important connection between PRC2-mediated histone methylation and PRC1-mediated ubiquitination.
- Non-canonical PRC1 complexes contain different accessory proteins and can be recruited to chromatin through mechanisms that do not require pre-existing H3K27me3. Many non-canonical PRC1 complexes contain RYBP or YAF2 and can have strong H2AK119ub-producing activity. Other PRC1-associated proteins, including KDM2B, AUTS2, and BCOR-related components, participate in distinct PRC1 configurations and influence their genomic targeting and regulatory functions.
- The relationship between RING1A/RING1B and PRC2 is therefore part of a broader network of Polycomb regulation. PRC2 uses EZH1 or EZH2 as catalytic components to establish H3K27 methylation, particularly H3K27me3, whereas PRC1 uses RING1A or RING1B to establish H2AK119ub. These two histone modifications are associated with different enzymatic activities but frequently occur within related Polycomb-regulated chromatin environments.
- The relationship between H2AK119ub and H3K27me3 is not simply a one-directional pathway. H3K27me3 can contribute to recruitment of canonical PRC1 through CBX proteins, while non-canonical PRC1 complexes can establish H2AK119ub independently of H3K27me3 and can contribute to PRC2 recruitment or activity in some contexts. This reciprocal interaction allows PRC1 and PRC2 to cooperate while retaining distinct recruitment mechanisms and biochemical functions.
- RING1B also has an important role in regulating chromatin architecture. Beyond simply serving as an enzyme that modifies histones, RING1B-containing PRC1 complexes can influence nucleosome organization and interactions between distant genomic regions. PRC1-mediated chromatin compaction and higher-order genome organization can help establish three-dimensional chromatin environments associated with Polycomb regulation. These structural functions are closely connected to the ability of Polycomb complexes to regulate groups of genes rather than isolated individual loci.
- H2AK119ub itself can influence chromatin in several ways. The modification can alter the properties of nucleosomes and provide a molecular signal recognized by other chromatin-associated proteins. H2AK119ub is also involved in the recruitment or stabilization of Polycomb-associated regulatory machinery at particular genomic regions. Its effects therefore extend beyond the chemical addition of ubiquitin and contribute to a broader chromatin-regulatory state.
- RING1A and RING1B are especially important during development because Polycomb-regulated genes frequently include genes involved in cell-fate determination and developmental patterning. During differentiation, cells must activate some developmental programs while maintaining repression of others. PRC1-mediated H2AK119ub contributes to the repression of genes that should remain inactive in particular cellular states, helping cells maintain stable patterns of gene expression.
- Polycomb regulation is also important in stem cells, where cells must maintain their developmental potential while preventing inappropriate activation of differentiation programs. RING1B-dependent H2AK119ub contributes to the repression of developmental genes in several stem-cell contexts. Changes in PRC1 composition or activity can alter the balance between self-renewal and differentiation by changing the chromatin environment at regulatory genes.
- RING1A and RING1B also participate in the maintenance of cellular identity. Once a cell has differentiated, its gene-expression program must be maintained despite ongoing cell division and changes in the cellular environment. Polycomb-mediated chromatin states provide one mechanism for maintaining repression of genes that are inappropriate for a particular lineage. RING1-dependent H2AK119ub is an important component of this epigenetic memory.
- The removal of H2AK119ub is also biologically important. Because histone ubiquitination is reversible, the level of H2AK119ub reflects a balance between ubiquitin ligase activity and deubiquitinating enzymes. BAP1, a deubiquitinating enzyme associated with the ASXL-containing Polycomb-related regulatory machinery, is an important regulator of H2AK119ub. The dynamic balance between RING1A/RING1B-mediated ubiquitination and deubiquitination allows Polycomb-associated chromatin states to change when gene-expression programs need to be altered.
- RING1B is also subject to regulation through interactions with numerous chromatin-associated proteins. These interactions influence its genomic localization, catalytic activity, and participation in different PRC1 complexes. Consequently, the biological effect of RING1B cannot be understood solely by measuring its abundance. The identity of the PRC1 complex in which RING1B functions is also important.
- The distinction between RING1A/RING1B activity and H2AK119ub is important when interpreting experimental results. RING1A and RING1B are proteins and enzymes, whereas H2AK119ub is a post-translational histone modification produced by their ubiquitin ligase activity. Measurements of RING1B occupancy, PRC1 binding, and H2AK119ub levels therefore provide related but distinct information about Polycomb regulation.
- Several experimental approaches are used to investigate RING1A and RING1B. Chromatin immunoprecipitation followed by sequencing can be used to map RING1B or H2AK119ub across the genome. CUT&RUN, CUT&Tag, and related chromatin profiling methods can provide complementary information about protein occupancy and histone modifications. Genetic deletion, depletion, or mutation of RING1A, RING1B, or other PRC1 components can then be combined with transcriptomic analyses to investigate effects on gene expression.
- Biochemical studies have also helped define the catalytic mechanism of PRC1. Structural and biochemical analyses show how the RING domains of RING1 proteins interact with PCGF proteins and components of the ubiquitination machinery. These interactions help explain how PRC1 recognizes nucleosomal substrates and selectively promotes H2AK119 monoubiquitination.
- RING1A and RING1B are also relevant to disease biology. Altered Polycomb regulation has been associated with developmental disorders and cancer, and changes in PRC1 composition or activity can affect cellular proliferation, differentiation, and gene-expression programs. Because RING1 proteins function within multiple PRC1 complexes, the consequences of their dysregulation can vary according to tissue type and cellular context.
- RING1B has additionally been studied in relation to transcriptional repression, chromatin accessibility, DNA damage responses, and genome organization. These functions illustrate the broader role of PRC1 beyond the establishment of H2AK119ub. Nevertheless, H2AK119ub remains the defining biochemical output most closely associated with the catalytic activity of RING1A and RING1B.
- RING1A and RING1B therefore occupy a central position in the PRC1 branch of the Polycomb system. By working with PCGF proteins and other PRC1 components, they establish H2AK119ub and contribute to the formation and maintenance of Polycomb-regulated chromatin. Their activities interact with PRC2, H3K27me3, chromatin architecture, developmental gene regulation, and epigenetic memory, illustrating how multiple molecular mechanisms cooperate to control stable yet reversible patterns of gene expression.
- Understanding RING1A and RING1B provides an important foundation for studying PRC1 diversity, H2AK119ub, Polycomb recruitment, and the relationship between PRC1 and PRC2. These proteins also provide a useful example of how an epigenetic regulator can combine enzymatic activity with chromatin organization to influence cell identity and developmental programs. Further study of RING1 proteins, PCGF proteins, canonical and non-canonical PRC1 complexes, and H2AK119ub deubiquitination continues to expand our understanding of Polycomb-mediated gene regulation.
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