Oncofusion

start / graph / gene-mcm2

Genemoderate confidence 3 of 5: One strong study, or several smaller consistent ones.Q84-pan-fusion-core

MCM2 (P49736) - replicative helicase subunit and parental-histone chaperone in the pan-MLL-fusion core, and a live gene_exact collision with MCM7

also called MCM2 · BM28 · CDCL1 · KIAA0030 · minichromosome maintenance complex component 2 · DNA replication licensing factor MCM2

MCM2 is part of the ring-shaped motor that unwinds DNA at replication forks, and it doubles as a chaperone that catches old histones as they come off and hands them back onto the new DNA. It co-purifies with every MLL fusion tested, and it is the protein in this set with the cleanest index-fusion measurement.

The same thing, for a scientist

MCM2 (P49736, 904 aa) is a subunit of the MCM2-7 replicative helicase and, through a dedicated N-terminal histone-binding domain, a chaperone for parental H3-H4 at the replication fork - the mechanism by which modified histones are recycled and epigenetic state is propagated through S phase. In Skucha 2018 it co-purified with all seven MLL fusions; the MLL-AF4 (= KMT2A::AFF1) call is p = 0.00708 with 12|14 spectra against a 0|2 negative control - the most solid index-fusion measurement of the twelve on the combination of p-value and spectral depth. A separate study places MLL-WDR5-RBBP5 complexes at replication origins co-localised with ORC and MCM2-7, with WDR5 or RBBP5 knockdown reducing MCM2-7 recruitment - wild-type MLL rather than the fusion, but the only independent tie between MCM2 and anything in the KMT2A family. Note the identifier trap: `gene_exact:MCM2` returns MCM7 first, because MCM7 carries MCM2 as a gene synonym.

Go deeper
The Skucha row

7 of 7 fusions. MLL-AF1p 0.00316 (16|14), MLL-AF4 0.00708 (12|14), MLL-AF9 0.00342 (28|27), MLL-CBP 0.0185 (11|17), MLL-EEN 0.0146 (24|39), MLL-ENL 0.00306 (23|34), MLL-GAS7 0.0287 (25|29); negative control 0|2 1. Unlike most of this beat, the index-fusion call is neither the weakest of the seven nor marginal, and it rests on 12 and 14 spectra rather than three or four.

What MCM2 does that could matter here

MCM2 carries a histone-binding domain that grips an H3-H4 tetramer by hijacking the surface nucleosomal DNA would use, and can co-chaperone an H3-H4 dimer with ASF1; the domain is required for MCM2-7 histone-chaperone function and for normal proliferation 2. In yeast, the Mcm2-Ctf4-Pol-alpha axis routes parental H3-H4 to the lagging strand, so the helicase decides where old, modified histones land 3. That is the mechanism by which chromatin state survives replication - which is the mechanism a fusion oncoprotein's aberrant chromatin programme would have to survive as well. This entry records that adjacency as a question, not as a finding: nothing in the literature tests whether a KMT2A fusion's marks are propagated by MCM2.

The only independent KMT2A-family tie

In a DNA re-replication system, components of the MLL-WDR5-RBBP5 methyltransferase complexes co-localised with the origin recognition complex and the MCM2-7 replicative helicase at replication origins, and siRNA reduction of WDR5 or RBBP5 lowered H3K4 methylation at origins and suppressed MCM2-7 recruitment 4. This is wild-type MLL complex activity, in a re-replication model driven by Geminin or CRL4-CDT2 knockdown, and it says nothing about a fusion - but it is the only published connection between MCM2-7 and the KMT2A machinery, and it runs in the direction MLL complex -> MCM2-7 loading rather than the reverse.

The identifier trap, recorded because it is live

gene_exact:MCM2 AND organism_id:9606 AND reviewed:true returns two reviewed human records and the wrong one is first: P33993, MCM7_HUMAN, primary gene MCM7, 719 aa, which carries MCM2 among its synonyms, ahead of P49736, MCM2_HUMAN, primary gene MCM2, 904 aa. A script taking the first data row gets MCM7 with no error. Length discriminates here (719 against 904), so verify-accessions.py would catch a swap - but only if the entry asserts the length. This collision is not in data/symbol-collisions.json as of 2026-09-21.

Facts and figures
uniprotP49736
length AA904
accession resolutionResolved live 2026-09-21 and it is a COLLISION: gene_exact:MCM2 AND organism_id:9606 AND reviewed:true returns TWO reviewed rows, with the wrong one first - P33993 MCM7_HUMAN, gene_primary MCM7, 719 aa, carrying MCM2 as a synonym - ahead of P49736 MCM2_HUMAN, gene_primary MCM2, 904 aa, synonyms BM28 CCNL1 CDCL1 KIAA0030. Only the primary gene name separates them; length (719 vs 904) then guards against a swap. The accession asserted here is P49736 and it matches Skucha's table. NOT in data/symbol-collisions.json as of 2026-09-21.
localizationNucleus
subnuclear localizationReplication foci / chromatin during S phase; no named subnuclear body.
localization evidenceUniProt P49736, fetched 2026-09-21: Nucleus with ECO:0000269 experimental evidence; Chromosome with ECO:0000305 only - a CURATOR INFERENCE, not an experiment - which is worth noting for a protein whose whole function is chromosomal.
shown for fusionKMT2A::AFF1 (MLL-AF4) by co-purification at p = 0.00708 with 12|14 spectra, plus all six other Skucha baits. NO experiment ties MCM2 to a KMT2A FUSION; the only KMT2A-family tie is to wild-type MLL-WDR5-RBBP5 complexes at replication origins.
graph contextMCM2 appeared in exactly one node file in this graph before this entry (grep -rl, 2026-09-21). gene-wdr5 exists and is the natural neighbour.
skucha 2018
{
  "bait": "MLL-AF4 (= KMT2A::AFF1)",
  "p_value": 0.00708,
  "spectral_counts": "12|14",
  "n_fusions_of_seven": 7,
  "negative_control_counts": "0|2",
  "per_bait": {
    "MLL-AF1p": "0.00316 (16|14)",
    "MLL-AF4": "0.00708 (12|14)",
    "MLL-AF9": "0.00342 (28|27)",
    "MLL-CBP": "0.0185 (11|17)",
    "MLL-EEN": "0.0146 (24|39)",
    "MLL-ENL": "0.00306 (23|34)",
    "MLL-GAS7": "0.0287 (25|29)"
  },
  "note": "The most even per-bait profile in this beat - every value between 0.003 and 0.029, every one on 11 or more spectra.",
  "source": "analyses/skucha-mll-fusion-interactome/results.json, re-derived from the cached MOESM4 xlsx on 2026-09-21"
}
cell types and states
[
  "Jurkat (human T-ALL) - AP-MS host, nuclear lysate",
  "human cells - MCM2 histone-binding-domain structures and proliferation requirement",
  "budding yeast - Mcm2-Ctf4-Pol-alpha parental histone routing",
  "human cells in induced DNA re-replication - MLL-WDR5-RBBP5 at origins with ORC and MCM2-7",
  "no KMT2A-rearranged cell of any kind"
]
bounded literature
{
  "query": "MCM2[tiab] AND (KMT2A[tiab] OR MLL[tiab] OR \"MLL-AF4\"[tiab] OR \"MLL-AF9\"[tiab])",
  "querytranslation": "\"MCM2\"[Title/Abstract] AND (\"KMT2A\"[Title/Abstract] OR \"MLL\"[Title/Abstract] OR \"MLL-AF4\"[Title/Abstract] OR \"MLL-AF9\"[Title/Abstract])",
  "count": 1,
  "on_topic_after_title_check": 1,
  "date": "2026-09-21",
  "tool": "NCBI esearch db=pubmed",
  "the_one_record": "PMID 27744293 - wild-type MLL complex and MCM2-7 at replication origins, cited as E4",
  "names_tried": [
    "MCM2"
  ],
  "positive_control": "the identical query shape with MEN1 returns 85",
  "bound": "Titles and abstracts only. The complex form MCM2-7 was not run as a separate query and could add records - the standing complex-subunit rule applies and this beat did not fully discharge it."
}
functionally screened in the source paper
{
  "_added": "king, cycle 48, 2026-09-21, after Q86 flagged that cycle-47 entries understate the record. Verified by me directly from the supplementary file, not from the paper's prose.",
  "screened": true,
  "library_symbol": "MCM2",
  "shrnas_for_this_gene": 6,
  "design": "Supplementary Table 6 / MOESM5 is 768 data rows, 128 unique gene symbols, EXACTLY 6 shRNAs each -- counted with openpyxl on 2026-09-21. Negative-selection RNAi screen in MLL-AF9-expressing MOLM-13.",
  "what_this_DOES_establish": "Every one of the 128 conserved MLL-fusion interactors, this protein included, was functionally tested against an MLL fusion. An entry saying 'nothing in the paper validates this prey' is true of BINDING and understates the record.",
  "what_this_does_NOT_establish": "A per-gene result. Scores are presented as heatmaps (Fig. 2c/2d) and no per-gene depletion value is tabulated, so for any individual gene the outcome is measured-not-reported. It is also MLL-AF9 MOLM-13, a myeloid line, not the index fusion and not B-lineage.",
  "absence_class_for_the_per_gene_score": "measured-not-reported"
}
How this could bite us back
  • MCM2 is part of the replicative helicase and is required by every dividing cell; it is a pan-essential gene and not a target.
  • If the fusion's marks are propagated through MCM2-dependent histone recycling, then interfering with recycling would perturb every epigenetic state in the cell, not just the oncogenic one.
  • An association with replication machinery in a doxycycline-induced, asynchronously cycling cell line is exactly the kind of result that can be a proliferation artefact rather than a property of the fusion.
Still open
  1. Are other MCM2-7 subunits, ORC components or CMG partners in the Skucha 960-protein network? A helicase-wide signature would say 'the fusion is on replicating chromatin' rather than 'the fusion binds MCM2'.
  2. Is the fusion's chromatin programme propagated through S phase by MCM2-mediated parental histone recycling? No experiment in any system has asked.
  3. Does the association depend on cell-cycle phase? A doxycycline-induced bait in an asynchronous Jurkat population cannot say, and a synchronised experiment could.
  4. The complex-form query MCM2-7 was never run against the KMT2A literature. Running it is one command and this beat did not do it.
Every source behind this entry (4)
  1. E1moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper

    MCM2 co-purified with all seven Strep-HA-tagged MLL fusions in isogenic Jurkat cells, with the MLL-AF4 (= KMT2A::AFF1) call at p = 0.00708 and 12|14 spectral counts against a 0|2 negative control.

    MLL-fusion-driven leukemia requires SETD2 to safeguard genomic integrity. · Skucha A, Ebner J, Schmoellerl J, Roth M, Eder T, Cesar-Razquin A, Stukalov A, Vittori S, Muhar M, Lu B, Aichinger M, Jude J, Mueller AC, Gyorffy B, Vakoc CR, Valent P, Bennett KL, Zuber J, Superti-Furga G, Grebien F · Nature Communications 2018
    PMID 29777171DOI
    What this evidence cannot show

    SYSTEM: the AP-MS host is JURKAT, a T-ALL line, whereas KMT2A::AFF1 disease is B-lineage infant leukaemia, so a partner that needs a B-cell or infant proteome cannot appear here and a T-lineage partner can appear spuriously. The bait is a Strep-HA-tagged, SINGLE-COPY, doxycycline-INDUCED transgene, not the endogenous fusion. Prey was recovered from bulk nuclear lysate, so co-purification is not evidence of a direct contact. INCLUSION RULE: the paper kept the top 300 interactions per bait by combined p-value rather than applying a p threshold (Methods, verbatim: "The 300 most significant interactions per bait were retained"). Measured by this beat by reading the cached Supplementary Table 5 xlsx directly on 2026-09-21: 545 of the 2,049 per-bait p-values in the table (26.6%) exceed 0.05, to a maximum of 0.175. This graph's own king analysis ana-the-index-fusion-interactome-is-not-distinctive-and-two-earlier-answers-were-artifacts found the MLL-AF4 column reaches deepest into the weak tail of the seven, so an MLL-AF4 p-value is systematically weaker than the same protein's p-value under another bait and should not be read as a weaker interaction. The negative control is not clean (0|2), and replication-machinery proteins are abundant in nuclear lysate from proliferating cells. Against that, this is the deepest index-fusion identification of the twelve. Values re-read from the cached xlsx on 2026-09-21.

    Evidence that argues against this (1)
    • IntAct has never curated this dataset (pubid:29777171 returns 0 rows against a working positive control), so no independent curator has re-examined these calls, and the raw data at ProteomeXchange PXD009338 have not been reanalysed here. Nothing in the paper validates this particular prey by an orthogonal assay: of the twelve proteins in this beat, only SETD2 is mentioned anywhere in the paper's body text (counted by regex over the PMC full text, 2026-09-21; SF3A3 appears once, as a named non-selective control). ProteomeXchange/PRIDE 2018
  2. E2established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paper

    Human MCM2 chaperones histones H3-H4 through a dedicated histone-binding domain that engages the H3-H4 tetramer at the surface used by nucleosomal DNA, can co-chaperone an H3-H4 dimer together with ASF1, and is required for MCM2-7 histone-chaperone function and normal cell proliferation.

    A unique binding mode enables MCM2 to chaperone histones H3-H4 at replication forks. · Huang H, Stromme CB, Saredi G, Hodl M, Strandsby A, Gonzalez-Aguilera C, Chen S, Groth A, Patel DJ · Nat Struct Mol Biol 2015
    PMID 26167883DOI
    What this evidence cannot show

    Crystal structures of MCM2 histone-binding-domain fragments with H3-H4, plus mutational analysis in human cells; the structures are of isolated domains, not the assembled CMG helicase. Not a haematopoietic or fusion system. Read from the abstract.

    Evidence that argues against this (1)
    • A histone-chaperone activity demonstrated for MCM2 in isolation does not establish that the fusion's own chromatin marks are propagated through it, which nobody has tested. Gan H et al. 2018
  3. E3strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

    The Mcm2-Ctf4-Pol-alpha axis routes parental H3-H4 tetramers to the lagging strand at replication forks; mutating the conserved histone-binding domain of Mcm2 enriches parental H3-H4 on the leading strand by impairing that transfer.

    The Mcm2-Ctf4-Polalpha Axis Facilitates Parental Histone H3-H4 Transfer to Lagging Strands. · Gan H, Serra-Cardona A, Hua X, Zhou H, Labib K, et al. · Mol Cell 2018
    PMID 30244834DOI
    What this evidence cannot show

    BUDDING YEAST, with mutants of Mcm2, Ctf4 and Pol-alpha primase. The human orthology is good but the strand-asymmetry result has not been shown in a leukaemic cell. Read from the abstract.

    Evidence that argues against this (1)
    • Strand-specific histone routing in yeast may not set the same asymmetry in human cells, where additional chaperones (POLE3/POLE4, FACT, DNAJC9) participate. Huang H et al. 2015
  4. E4moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper

    Components of the MLL-WDR5-RBBP5 methyltransferase complexes co-localise with the origin recognition complex and the MCM2-7 replicative helicase at replication origins, and siRNA reduction of WDR5 or RBBP5 lowers H3K4 methylation at origins and suppresses MCM2-7 recruitment.

    PMID 27744293DOI
    What this evidence cannot show

    WILD-TYPE MLL complex, not a fusion - and the system is DNA RE-replication induced by knocking down Geminin or CRL4-CDT2, which is an abnormal state chosen to amplify licensing phenotypes. The knockdowns are of WDR5 and RBBP5, not of MLL itself, and WDR5 and RBBP5 are shared by all six KMT2 complexes, so the result is not attributable to KMT2A. Read from the abstract. Recorded because it is the only published link between MCM2-7 and the KMT2A machinery, and its direction is MLL complex to helicase, not helicase to fusion.

    Evidence that argues against this (1)
    • WDR5 and RBBP5 are shared across the KMT2 family and have KMT2-independent functions, so this result cannot be assigned to KMT2A, let alone to a KMT2A fusion. Skucha A et al. 2018
Connected to