SKP1 — a pan-essential housekeeping adaptor that is also a structural subunit of PRC1.1, which makes it the one PRC1.1 member that can never be a target
also called SKP1 · SKP1A · OCP2 · TCEB1L · EMC19 · p19A · S-phase kinase-associated protein 1
SKP1 is a small adaptor protein that every human cell uses constantly to help tag proteins for destruction. It is also, unexpectedly, a genuine structural part of the PRC1.1 gene-silencing machine — which means you can never drug it, because removing it kills every cell equally.
The same thing, for a scientist
SKP1 (P63208, 163 aa) is the SKP1-CUL1-F-box (SCF) adaptor that links an F-box protein to cullin-1. It is also a **structural subunit of PRC1.1**: the minimal four-component PRC1.1 reconstituted by Wong et al. is a **KDM2B/SKP1 heterodimer** plus a **BCORL1/PCGF1 heterodimer**, and SKP1 residues **2-163 are modelled in the 2.55 A crystal structure PDB 5JH5** [E1][E2]. The reason is that KDM2B is itself an F-box protein (FBXL10), so the same F-box that would recruit SKP1 into an SCF ligase instead, or additionally, builds the DNA-binding half of PRC1.1 — a point the structure paper makes explicitly [E1]. UniProt annotates SKP1 aa **104-163** as the F-box-binding region [E3]. The dependency consequence is decisive and negative: SKP1 is **pan-essential** (mean gene effect **-1.2813** across 1,208 lines) with **no KMT2A selectivity at all** (difference -0.0132, rank 7,404 of 17,728, 41.8th percentile) [E4]. And it is essentially unstudied in this disease: `(MLL OR KMT2A) AND (SKP1 OR SKP1A OR OCP2 OR TCEB1L)` returns **1 record** [E5].
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.
I have never read one of these pictures before
A protein is one long chain of amino acids that folds up. The ribbon traces that chain from one end to the other; it is not a wire, it is a simplification of where the backbone runs. Drag to rotate, scroll to zoom.
Domains are the stretches of chain that do a particular job, and they are what the coloured blocks above the picture mark out. Click one and the view flies to it. In this project the important question about any domain is usually whether the fusion still has it — the labels say lost where it does not.
Anything in yellow sticks is a bound small molecule, which is usually the drug.
Why a housekeeping adaptor is in a Polycomb complex at all
KDM2B carries an F-box. In the canonical use of that motif, an F-box protein docks onto SKP1, which docks onto cullin-1, assembling an SCF E3 ubiquitin ligase. In PRC1.1 the same KDM2B/SKP1 pairing is a targeting module: KDM2B's ZF-CxxC domain reads non-methylated CpG islands, and the KDM2B/SKP1 heterodimer is one of the two halves that must be combined to reconstitute PRC1.1 in vitro 1.
Wong et al. state the implication directly — the structure 'suggests how KDM2B might simultaneously function in PRC1.1 and an SCF ubiquitin ligase complex' 1. That is an unresolved and interesting piece of biology: it means KDM2B may partition between a chromatin-silencing role and a protein-degradation role, and anything that changes SKP1 availability could shift that partition.
The negative result this entry is for
This beat's job is to enumerate the PRC1.1 module completely, and completeness includes writing down the members that are dead ends. SKP1 is the clearest dead end in the complex:
- Pan-essential. Mean gene effect -1.281 across 1,208 lines 4. Every cell needs it.
- Zero selectivity. KMT2A-rearranged mean -1.3868 against other-leukaemia -1.3737; a difference of -0.013 that sits at the 42nd percentile, i.e. indistinguishable from the middle of the genome 4.
- No literature. One PubMed record across four symbol spellings 5.
The positive contribution is the discrimination it supports: three PRC1.1 members (PCGF1, BCOR, BCORL1) sit on the anti-dependency side of the scan, and this one sits at dead centre while being lethal to everything. That pattern is what a complex looks like when its specific subunits are restraints and its shared subunits are housekeeping — and it is a useful check on complex-level reasoning, because a naive 'PRC1.1 is essential' inference drawn from SKP1's -1.28 would be entirely an artefact of SCF.
Cell type, cell state, localisation and epigenetic readout
| Axis | Documented | Where |
|---|---|---|
| Cell type | Ubiquitous; no KMT2A-rearranged system studied | 45 |
| Cell state | Not established in this context | — |
| Subcellular | Nucleus and cytoplasm (SCF is cytoplasmic and nuclear); within PRC1.1 it is nuclear and chromatin-associated by inference | 1 |
| Subnuclear | Not established. | — |
| Epigenetic readout | None of its own. SKP1 is catalytically inert; the PRC1.1 mark is H2AK119ub deposited by RING1A/B. | 1 |
| Structural position | Modelled aa 2-163 in PDB 5JH5, paired with KDM2B aa 1059-1336 | 2 |
| uniprot | P63208 |
|---|---|
| gene symbol | SKP1 |
| protein name | S-phase kinase-associated protein 1 |
| length AA | 163 |
| alphafold ID | AF-P63208-F1 |
| accession resolution | UniProt REST query gene_exact:SKP1 AND organism_id:9606 AND reviewed:true, run 2026-09-19; one reviewed hit; primary gene name read back as SKP1 and length 163 confirmed from the same fetched record, and independently consistent with RCSB modelling SKP1 residues 2-163 in 5JH5. |
| complex | shared between the SCF (SKP1-CUL1-F-box) ubiquitin ligase and PRC1.1 |
| classification | shared housekeeping adaptor and structural PRC1.1 subunit; NOT an interactor of KMT2A::AFF1 and not a candidate target |
| classification reason | pan-essential with zero KMT2A selectivity; no published link to any KMT2A fusion |
| interaction evidence class | in-vitro reconstitution; X-ray crystallography (5JH5) |
| shown for fusion | none |
| epigenetic readout | none of its own |
PDB IDS
[ "5JH5" ]
aliases retired or alternate
[ "SKP1A", "OCP2", "TCEB1L", "EMC19", "p19A" ]
complex partners
[ "gene-kdm2b", "gene-pcgf1", "gene-bcorl1", "gene-bcor" ]
domains
[
{
"name": "F-box-binding region",
"start": 104,
"end": 163,
"source": "UniProt P63208, fetched 2026-09-19"
}
]localization
{
"subcellular": "nucleus and cytoplasm (SCF); nuclear and chromatin-associated within PRC1.1 by inference",
"subnuclear": "not established",
"chromatin_targeting": "indirect, as the partner of the KDM2B F-box; DNA contact is made by the KDM2B ZF-CxxC domain"
}essentiality
{
"depmap_scan": "analyses/depmap-kmt2a-selective-scan-full",
"pan_essentiality_all_lines": -1.2813,
"n_all_lines": 1208,
"mean_kmt2a_rearranged": -1.3868,
"mean_other_leukemia": -1.3737,
"kmt2a_selectivity_difference": -0.0132,
"rank": 7404,
"n_scanned": 17728,
"percentile": 41.764,
"interpretation": "pan-essential, zero selectivity, floor effect - an undruggable housekeeping node"
}enumeration record count
{
"query": "(MLL OR KMT2A) AND (SKP1 OR SKP1A OR OCP2 OR TCEB1L)",
"records": 1,
"date": "2026-09-19"
}depmap kmt2a selectivity
{
"chronos_mean_kmt2a_rearranged": -1.3868,
"chronos_mean_other_leukaemia": -1.3737,
"difference": -0.0132,
"pan_essentiality_all_lines": -1.2813,
"selectivity_rank": 7404,
"rank_denominator": 17728,
"provenance": "Joined 2026-09-21 from analyses/depmap-kmt2a-selective-scan-full (generated 2026-09-19T10:12:06Z), the project's own genome-wide scan over 11 KMT2A-rearranged and 43 other leukaemia DepMap lines. NOT re-fetched and NOT independent of that scan: every caveat it carries applies here, including that the KMT2A-rearranged arm is a small number of lines drawn from nine individuals, that the rank denominator is 17,728 genes, and that a difference is not a dependency. Added because only 26 of 308 gene entries carried this number, which made any KMT2A-selectivity question answerable for 8% of the corpus.",
"how_to_read": "A negative difference means MORE required in KMT2A-rearranged lines than in other leukaemia lines. A rank near 17,728 is ANTI-selective. Neither is evidence of a fusion-driven dependency on its own: check pan_essentiality_all_lines before calling anything selective, and note that a paralogue-redundant gene can score near zero for reasons that have nothing to do with this disease - see ana-the-paralogue-redundancy-excuse-is-not-tested-and-my-proxy-decided-the-answer."
}- SKP1 is required by every cell at a gene effect of -1.28. Any agent that reduced SKP1 function would be a general cytotoxic with no therapeutic window, and the PRC1.1 rationale would contribute nothing to its selectivity.
- Because SKP1 is shared with SCF, any observed effect of perturbing it will be dominated by disrupted protein degradation, and a PRC1.1 interpretation of such an experiment would almost certainly be wrong.
- This entry is a reminder that complex-level essentiality averages are misleading: averaging SKP1's -1.28 with PCGF1's +0.06 would produce a number describing nothing real.
- How does KDM2B partition between SCF and PRC1.1, and does that partition shift in a KMT2A-rearranged cell? Wong et al. raise the question and nobody has measured it.
- Is there any PRC1.1-specific surface on SKP1 that differs from its SCF-engaged surface? If not, SKP1 can never be selectively targeted in this complex and the question is closed.
- Does SKP1 abundance limit PRC1.1 assembly, making it a rate-setting rather than merely structural subunit?
- E1established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paper
A minimal four-component PRC1.1 can be assembled by combining a DNA-binding KDM2B/SKP1 heterodimer with a BCORL1/PCGF1 heterodimer; the crystal structure of KDM2B/SKP1/BCORL1/PCGF1 shows the BCORL1 PUFD positioning residues preceding the PCGF1 RAWUL to create an extended KDM2B interface unique to PCGF1-containing PRC1.1, and suggests how KDM2B might simultaneously function in PRC1.1 and in an SCF ubiquitin ligase complex.
KDM2B Recruitment of the Polycomb Group Complex, PRC1.1, Requires Cooperation between PCGF1 and BCORL1 · Wong SJ, Gearhart MD, Taylor AB, Nanyes DR, Ha DJ, Robinson AK, Artigas JA, Lee OJ, Demeler B, Hart PJ, Bardwell VJ, Kim CA · Structure 24(10):1795-1801 2016What this evidence cannot show
Abstract fetched and read on 2026-09-19; full text not read. In-vitro assembly of truncated constructs plus crystallography, with no cellular validation and no leukaemia system. The SCF-versus-PRC1.1 partition of KDM2B is offered by the authors as a suggestion from the structure, not as a measured partition.
Evidence that argues against this (1)
- In-vitro reconstitution selects for the subcomplexes that survive purification. A 2024 study reports the BCOR-PRC1.1 enzymatic core is tethered to KDM2B through calcium-modulated liquid-liquid phase separation, a regime in which a fixed stoichiometric four-component assembly is not the whole description of the complex. Chen R et al. 2024
- E2established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database
RCSB PDB entry 5JH5, X-ray diffraction at 2.55 A, models SKP1 (UniProt P63208) residues 2-163 alongside KDM2B (Q8NHM5) 1059-1336, PCGF1 (Q9BSM1) 150-255 and BCORL1 (Q5H9F3) 1668-1785; the primary citation is PMID 27568929, DOI 10.1016/j.str.2016.07.011.
RCSB PDB entry 5JH5 - Structural Basis for the Hierarchical Assembly of the Core of PRC1.1 · RCSB Protein Data Bank; entry and polymer-entity alignment records queried via data.rcsb.org 2016What this evidence cannot show
Entity descriptions, UniProt accessions and modelled reference ranges fetched from data.rcsb.org on 2026-09-19 and copied from the same fetched records. That SKP1 is modelled essentially full-length (2-163 of 163) means the crystal says little about which part of SKP1 is dispensable.
Evidence that argues against this (1)
- No structure exists of PRC1.1 containing RING1A/B or a nucleosome, so 5JH5 shows the targeting module only. SKP1's presence in a crystallised targeting module does not establish that SKP1 is required for PRC1.1 function on chromatin in a cell - a SKP1-independent recruitment route has not been excluded because it has not been tested. van den Boom V et al. 2016
- E3established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database
UniProtKB P63208 (SKP1_HUMAN, S-phase kinase-associated protein 1) is 163 aa and annotates a disordered region at aa 63-83 and a region at aa 104-163 that interacts with the F-box domain of F-box proteins.
UniProtKB P63208 (SKP1_HUMAN), S-phase kinase-associated protein 1 · UniProt Knowledgebase, reviewed (Swiss-Prot) 2026What this evidence cannot show
Record fetched 2026-09-19; primary gene name read back as SKP1 and length 163 confirmed from the same fetched record. The F-box-binding region is a curator annotation aggregating SCF structural work, and it does not distinguish the SCF use of that surface from the PRC1.1 use.
Evidence that argues against this (1)
- If the same aa 104-163 surface serves both SCF and PRC1.1, the two are mutually exclusive on a single SKP1 molecule, and the relative abundance of F-box proteins would set the partition. No measurement of that partition exists in any cell, let alone a leukaemic one, so the mechanistic picture in this entry is a structural inference. Wong SJ et al. 2016
- E4strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.database
In the project's genome-wide KMT2A-rearranged selectivity scan of 17,728 genes, SKP1 is pan-essential with a mean gene effect of -1.2813 across 1,208 lines and shows no KMT2A selectivity: KMT2A-rearranged mean -1.3868 against other-leukaemia mean -1.3737, a difference of -0.0132, rank 7,404 (41.764th percentile). For contrast, the PRC1.1-specific subunits in the same scan sit on the opposite side: PCGF1 +0.1448 (rank 17,405), BCOR +0.1019, BCORL1 +0.0609.
Genome-wide KMT2A-rearranged selectivity scan, 17,728 genes (DepMap Chronos via Open Targets) · Broad Institute DepMap / Open Targets Platform; analyses/depmap-kmt2a-selective-scan-full 2026What this evidence cannot show
Numbers read out of analyses/depmap-kmt2a-selective-scan-full/results.json on 2026-09-19. A difference statistic is least informative where every line dies: at a mean effect of -1.38 in both groups there is a floor effect that can compress or invert the sign, so 'no selectivity' here is partly an artefact of the assay's dynamic range and should not be cited as a measured absence of selectivity.
Evidence that argues against this (1)
- The floor-effect caveat is not hypothetical for this gene. SKP1's essentiality comes overwhelmingly from SCF, a pathway unrelated to PRC1.1, so the scan is measuring the wrong function. If SKP1 had a KMT2A-specific PRC1.1 role, this assay could not see it, and the entry's conclusion that SKP1 is undruggable rests on the pan-essentiality rather than on the selectivity number. Wong SJ et al. 2016
- E5moderate confidence 3 of 5: One strong study, or several smaller consistent ones.database
PubMed returns 1 record for '(MLL OR KMT2A) AND (SKP1 OR SKP1A OR OCP2 OR TCEB1L)' as of 2026-09-19, so SKP1 is effectively unstudied in KMT2A-rearranged leukaemia.
PubMed E-utilities esearch record count for (MLL OR KMT2A) AND (SKP1 OR SKP1A OR OCP2 OR TCEB1L), run for this beat · NCBI PubMed, queried 2026-09-19 2026What this evidence cannot show
Counted-absence claims are only as good as the symbol set. Searched: SKP1, SKP1A, OCP2, TCEB1L. Not searched: p19A, EMC19, SKP1p, and the several ways an older paper might write 'Skp1' in a non-indexed position. The count is a floor, not a measurement.
Evidence that argues against this (1)
- The absence of a literature is also partly an artefact of how SCF papers are indexed: SKP1 appears in thousands of ubiquitin-ligase papers, and a KMT2A-relevant observation could be buried in one without SKP1 and KMT2A ever co-occurring in an indexed field. The claim 'unstudied in this disease' is defensible; the claim 'no relevant data exist' is not. NCBI PubMed, queried 2026-09-19; finding originally made by this project's non-elongation-partners beat, cycle 40 2026
structural subunit; modelled aa 2-163 in PDB 5JH5 as the KDM2B partner
SKP1 F-box-binding region (aa 104-163) docks the KDM2B F-box; the same motif that would build an SCF ligase
- related to →KMT2A::AFF1 (MLL-AF4), t(4;11)(q21;q23)
NOT an interactor: pan-essential (-1.281), zero KMT2A selectivity, 1 PubMed record across four symbol spellings