RING1 (RING1A) - the paralogue that is not RING1B, and the reason a substring search for 'RING1' in this graph returns the wrong gene

This is a prediction, not a measurement. No one has seen this protein in this shape. The colours say how much the software trusts itself, and that is worth reading before anything else — the orange stretches are places the model is effectively saying this part has no fixed shape.

• A RING1B-selective inhibitor would be phenocopied away by RING1, because the two are redundant for H2AK119ub deposition - any PRC1-catalytic drug programme has to hit both, which widens the on-target footprint to every PRC1 flavour including those required for normal haematopoiesis.
• Conversely, a dual RING1/RING1B inhibitor removes the machine through which a menin inhibitor silences its targets, so it is a candidate pharmacological antagonist of menin inhibition rather than a partner for it.
• Because the disease-relevant genetics are double knockouts, any biomarker built on one of the two genes will be uninterpretable in a patient where the other is intact.

1. Is RING1 non-redundant with RNF2 anywhere in KMT2A-rearranged leukaemia? No single-gene RING1 perturbation in this disease was found; every result is a double loss, so the question has not been asked rather than answered.
2. Does the RING1 hit in the GCB-DLBCL CRISPRi screen reproduce in a B-lineage KMT2A-rearranged line? That is the cheapest test of whether RING1 carries independent weight in a lymphoid chromatin-drug context.
3. Do RING1 and RING1B partition between PRC1 flavours - is one of them the preferred catalytic subunit of PRC1.1 specifically? A PCGF1 immunoprecipitation blotted for both would answer it in a day and would tell this project which gene its PRC1.1 claims are really about.

1. E1strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

   Genetic depletion of both Ring1a and Ring1b - the two H2A ubiquitin ligase subunits of PRC1 - is what was required to show that PRC1 activity and H2AK119 monoubiquitination support the leukaemogenic potential of Hox-activating and non-Hox-activating fusion proteins in mice.

   Maintenance of leukemic cell identity by the activity of the Polycomb complex PRC1 in mice. · Rossi A, Ferrari KJ, Piunti A, Jammula S, Chiacchiera F, Mazzarella L, et al. · Sci Adv 2016
   PMID 27730210DOI
   ▸What this evidence cannot show

   Mouse. The double depletion is the point and also the limitation: it removes every PRC1 flavour simultaneously, so it attributes nothing to RING1 specifically and nothing to PRC1.1 specifically. The fusions studied are Hox-activating (MLL-AF9 class) and non-Hox-activating, not KMT2A::AFF1.

   ▸Evidence that argues against this (1)

   • The therapeutic sign is reversed for the PRC1.1 flavour in KMT2A-rearranged AML under drug: loss of PCGF1 or BCOR confers menin-inhibitor resistance rather than impairing the leukaemia. A conclusion that 'PRC1 sustains the leukaemia' therefore cannot be carried to 'inhibiting PRC1 would treat it'. Zhou X et al. 2024
2. E2moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper

   An EZH2-inhibition-anchored genome-wide CRISPR interference screen in germinal-centre B-cell-like DLBCL identified multiple genes encoding non-canonical PRC1 components, including USP7, KDM2B, RING1 and PCGF1.

   DOT1L Shapes ncPRC1-Target Gene Repression to Maintain Germinal Center B Cell Identity of Diffuse Large B cell Lymphoma. · Gobel C, Niccolai R, Gregoricchio S, de Groot MHP, Kneefel SFK, Kreft M, et al. · Blood 2026
   PMID 42213647DOI
   ▸What this evidence cannot show

   GCB-DLBCL, not leukaemia, and the screen is anchored on EZH2 inhibition rather than on a menin or DOT1L inhibitor. Read at abstract level for this entry, so the effect size and direction for RING1 individually are not established here - only that the gene was called as a hit. A CRISPRi screen hit is a modifier, not a demonstration of non-redundancy with RNF2, because RNF2 may simply not have scored in that library or that context.

   ▸Evidence that argues against this (1)

   • Redundancy is the default expectation for this pair: the mouse leukaemia genetics required double Ring1a/Ring1b depletion to produce a phenotype at all, so a single-gene RING1 hit in one screen is not by itself evidence that RING1 carries non-redundant function, and could reflect library or context-specific sensitivity. Rossi A et al. 2016
3. E3weak confidence 2 of 5: Preliminary, small, indirect, or not yet peer reviewed.paper

   RING1, together with EZH2 and BMI1, is overexpressed in myelodysplastic syndromes and AML relative to non-clonal cytopenias, and its overexpression associates with poor prognostic scoring; decitabine treatment reduced EZH2 and RING1 expression.

   Overexpression of the EZH2, RING1 and BMI1 genes is common in myelodysplastic syndromes: relation to adverse epigenetic alteration and poor prognostic scoring. · Xu F, Li X, Wu L, Zhang Q, Yang R, Yang Y, et al. · Ann Hematol 2011
   PMID 21125401DOI
   ▸What this evidence cannot show

   Transcript-level expression association in MDS/AML, 2011, with no KMT2A-rearranged subgroup and no functional perturbation. Graded weak because an expression difference against a non-clonal-cytopenia comparator is confounded by blast fraction, and the decitabine effect on RING1 is an observation in treated patients, not a mechanism. Cited to bound the RING1-specific haematological literature, not to support a claim about this disease.

   ▸Evidence that argues against this (1)

   • No published counter-study of this specific association was found by this beat. Recorded as an unopposed weak claim rather than a supported one: the absence of a contradicting paper here reflects that almost nobody has measured RING1 separately from RNF2 in myeloid malignancy, not that the finding has been tested and held. The structural point stands against it - RING1 and RING1B are redundant, so a RING1 transcript difference has no established functional interpretation. Rossi A et al. 2016
4. E4established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database

   UniProt reviewed human record: RING1 is Q06587, entry name RING1_HUMAN, primary gene name RING1, synonyms RING1A and RNF1, 406 aa, recommended protein name 'E3 ubiquitin-protein ligase RING1' with alternative names 'Polycomb complex protein RING1' and 'RING finger protein 1'; the paralogue RNF2 is Q99496, entry name RING2_HUMAN, 336 aa, alternative name 'RING finger protein 1B'.

   UniProtKB reviewed human record for RING1 (Q06587), resolved by gene_exact:RING1 AND organism_id:9606 AND reviewed:true with gene_primary and length read back · UniProt Consortium · UniProtKB 2026
   ▸What this evidence cannot show

   A database fact, fetched 2026-09-20. It is opposable on scope but not on content: it states what the curated record says today and nothing about how any individual paper used the string 'RING1'. Papers published before the RING1A/RING1B convention stabilised may use either spelling for either gene, and no lookup resolves an ambiguous source document.

   ▸Evidence that argues against this (1)

   • The database cannot disambiguate the primary literature. Brief rule 66 documents the worst version of this in the family this graph is about - KMT2B and KMT2D each carry BOTH the MLL2 and MLL4 aliases and each protein name carries the other's number - and establishes that when a paper's usage is ambiguous the correct outcome is to record it unresolved rather than to resolve it from the database. Xu F et al. 2011
5. E5moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper

   Fluorescently tagged RING1, together with the CBX proteins and BMI1, accumulates in nuclear foci - Polycomb bodies - in human U2OS cells, and FRAP separates two behaviours: outside the foci PcG dynamics is governed by diffusion as complexes plus transient binding, while recovery inside the foci is substantially slower and the slow-binding amplitudes scale with focus size and intensity. The foci are therefore a kinetically distinct subnuclear compartment, which is the strongest subnuclear statement available for RING1.

   PRC1 components exhibit different binding kinetics in Polycomb bodies. · Vandenbunder B, Fourré N, Leray A, Mueller F, Völkel P, Angrand PO, et al. · Biol Cell 2014
   PMID 24460908DOI
   ▸What this evidence cannot show

   Human U2OS osteosarcoma cells with fluorescently TAGGED constructs, so the foci are reported for an exogenous protein at non-endogenous levels - the condensate-evidence caution applies, and FRAP recovery on its own cannot distinguish a phase-separated body from binding to spatially clustered sites. Nothing haematopoietic. The paper does not separate RING1 from RNF2/RING1B behaviourally.

   ▸Evidence that argues against this (1)

   • Polycomb bodies are not a free-standing address that RING1 chooses; the compartment is built upstream of PRC1 and can be dismantled by perturbing the other complex. PcG bodies overlie regions of PERICENTRIC HETEROCHROMATIN, and the PRC2 members EED and EZH2 - plus the maintenance DNA methyltransferase DNMT1 - are required for BMI1 recruitment to them. So 'RING1 localises to Polycomb bodies' is conditional on PRC2 and on DNA methylation, and in a cell where PRC2 is perturbed - which is exactly the situation under an EZH2 or EED inhibitor - the address may not exist. An entry that records the focus without the dependency would predict the wrong result from a PRC2-inhibitor experiment. Hernández-Muñoz I et al. 2005
6. E6moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper

   UniProt Q06587's 'Nucleus speckle' term for RING1 should not be relied on. It rests on a single coded citation, PubMed:21282530, which is a tandem-affinity-purification and MS/MS interaction-proteomics study defining PRC1 complexes and whose abstract describes no imaging experiment; and no speckle literature corroborates it - RING1[tiab] AND ("nuclear speckle"[tiab] OR "nuclear speckles"[tiab]) returns 0 records (2026-09-21).

   Interaction proteomics analysis of polycomb proteins defines distinct PRC1 complexes in mammalian cells. · Vandamme J, Völkel P, Rosnoblet C, Le Faou P, Angrand PO · Mol Cell Proteomics 2011
   PMID 21282530DOI
   ▸What this evidence cannot show

   This is a criticism of a database annotation made from the cited paper's ABSTRACT plus a literature bound, not from the paper's figures - the study may well contain a localisation panel that the abstract does not mention, which is precisely the rule-80 blind spot. The claim made here is therefore the narrow one: the speckle term is not supported by anything retrievable, so it should not be quoted as RING1's subnuclear address. It is not a claim that RING1 is absent from speckles.

   ▸Evidence that argues against this (1)

   • Against treating this as a defect in UniProt: an ECO:0000269 code does not promise that the cited paper's headline is your fact, only that a curator read an experiment in it, and this graph's own rule 91 documents four cases of exactly that on its central proteins. The more useful reading is that the speckle term and the Polycomb-body result are not necessarily in conflict - a protein can be in both - and the reason to prefer Polycomb bodies here is not that the speckle call is false but that the PcG-body result is reproducible, quantified by FRAP, and mechanistically anchored to a PRC2 dependency, while the speckle call has no retrievable supporting observation at all. Vandenbunder B et al. 2014
7. E7moderate confidence 3 of 5: One strong study, or several smaller consistent ones.database

   No RING1 localisation result exists in any KMT2A-fusion context. Measured 2026-09-21: (RING1[tiab] OR RING1A[tiab] OR RNF1[tiab]) AND (KMT2A[tiab] OR MLL[tiab] OR "MLL-AF4"[tiab] OR "MLL-AF9"[tiab] OR "MLL-ENL"[tiab] OR "MLL-AF10"[tiab] OR "t(4;11)"[tiab] OR "t(9;11)"[tiab]) AND (localization[tiab] OR localisation[tiab] OR subnuclear[tiab] OR nuclear[tiab] OR nucleolar[tiab] OR speckle[tiab] OR speckles[tiab] OR "PML bodies"[tiab] OR chromatin-bound[tiab] OR cytoplasmic[tiab]) returns 0 records; the unscoped pair (RING1[tiab] OR RING1A[tiab]) AND (KMT2A[tiab] OR MLL[tiab] OR "MLL-AF9"[tiab] OR "MLL-AF4"[tiab]) returns only 3, which is the operand control showing how thin the intersection is to begin with.

   PubMed E-utilities esearch, 2026-09-21. alias-aware over RING1, RING1A and RNF1; the operand control was run so the zero is not being read off an empty intersection of two large sets (rule 67 item 2) · NCBI PubMed 2026
   ▸What this evidence cannot show

   Bounded by titles and abstracts only. 'RING1' is also the string this graph must keep apart from RNF2/RING1B and from the PRC1 complex name - data/symbol-collisions.json carries both rows - so this count is over the gene symbol and its aliases, not over the complex, and a PcG-body imaging paper framed at the level of 'PRC1' would be unreachable from it (rule 64). Rule-67 positive control for this query SHAPE: the identical construction, run over all sixteen genes of this tranche on the same day, returned non-zero for seven of them - H2AZ1 1, EED 2, CHAF1B 1, CEBPA 3, TIFAB 1, SAMHD1 1, PROM1 1 - so the instrument can return a one. The querytranslation was read back on every run and confirms the quoted cytogenetic terms expand to "t 4 11"[Title/Abstract] and "t 9 11"[Title/Abstract] and not to a UID filter (rule 95); every term carries its own [tiab] tag rather than sitting inside a parenthesised group (rule 94).

   ▸Evidence that argues against this (1)

   • The complex-level query is the one that can break this absence and it was not run as a counted quantity, which is a real limitation of the bound rather than a rhetorical one: rule 64 exists because gene-ssrp1 recorded a false absence for exactly this reason. Note also that this graph already holds a localisation-polycomb-bodies-kmt2a-r node, so somebody has previously judged the Polycomb-body question relevant to this disease; the zero above means no paper names RING1 and a KMT2A fusion and a compartment in one abstract, not that the compartment is unstudied here. The functional side is well covered - Ring1a/Ring1b double depletion collapses leukaemic identity in Hox-activating fusion leukaemia - so the gap is specifically imaging, in the index disease. Rossi A et al. 2016

• causes →H2AK119ub - the mark every PRC1.1 claim in this graph rests on, named in fifteen entries and written in none until now

  RING1A is the redundant paralogous E3; only double Ring1a/Ring1b loss abolishes the mark

• related to →RNF2 (RING1B) — the one catalytic subunit shared by every PRC1 flavour, which is why the genetics point two ways at once

  redundant paralogous E3 ligases; 406 aa vs 336 aa; 'RING1B' is RNF2, not RING1

• part of →PRC1.1 — the complex this graph has been leaning on, now enumerated subunit by subunit, and the enumeration changes the conclusion

  alternative catalytic RING subunit of PRC1.1 (and of every PRC1 flavour)

• related to →KMT2A-rearranged acute myeloid leukaemia in children and infants

  only as half of a Ring1a/Ring1b double loss; no RING1-specific experiment exists in this disease

• co-occurs with →EZH2 - the Polycomb enzyme that collaborates with the fusion instead of opposing it, and that no single-agent inhibitor can switch off

  co-overexpressed with EZH2 and BMI1 in MDS/AML with adverse prognostic scoring

• ← inhibitsThere is no selective PRC1 catalytic inhibitor - the entire chemistry is one 2013 tool compound and its analogues, and it hits both paralogues by design

  the same compound hits the paralogue, by design given their redundancy

• ← depends onThe chromatin exchange at a menin-inhibited fusion site, measured in one experiment: H2AK119ub and H3K27me3 in, H3K4me3 out, in proportion to how much fusion left - and PCGF1 loss attenuates the in-fill without abolishing it

  RING1A/B is the ligase; Q117 measured its occupancy rising 1.3808-fold at the same quartile

• related to →Polycomb bodies — indirect evidence via CBX8, undercut by the finding that CBX8-PRC1 condensates are dissolved rather than built by the rest of PRC1

  Tagged RING1 forms Polycomb bodies with FRAP-slow internal kinetics in human U2OS cells (PMID 24460908); the address requires PRC2 (PMID 16314526). Nothing imaged in a blast (Q87 2026-09-21)

• depends on →EED - the PRC2 subunit this disease actually needs, with drugs in the clinic and zero leukaemia studies

  PRC1 recruitment to Polycomb bodies requires the PRC2 members EED and EZH2 and DNMT1 (PMID 16314526), so RING1's subnuclear address is conditional on PRC2

• related to →Chromocentres and pericentromeric satellite heterochromatin — no KMT2A evidence, but the AT-hook argument says there should be

  PcG bodies are described as located on regions of pericentric heterochromatin (PMID 16314526)

• ← related toCBX8 — the one place in this interactome where two good papers flatly disagree, and DepMap takes a side

  SAME UNIPROT CITATION, DIFFERENT VERDICT - the per-gene nature of a rule-91 audit. PMID 21282530, a CBX-family TAP-MS study with no imaging, is UniProt's sole source for CBX8's bare 'Nucleus' (acceptable if imprecise) and for RING1's specific 'Nucleus speckle' (not adopted by tranche 4, and RING1 against nuclear speckles returns 0). One paper, one good use and one bad one (Q95 2026-09-22)