Oncofusion

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Proteinmoderate confidence 3 of 5: One strong study, or several smaller consistent ones.Q5d-interactome3

TRRAP — a 3,859-residue DotCom subunit that every cell needs and no KMT2A cell needs more

also called TRRAP · Transformation/transcription domain-associated protein · PAF400 · TR-AP

TRRAP is an enormous scaffolding protein found inside the H3K79 methylation complex, and also inside several other complexes that acetylate histones. Every cancer cell line tested dies without it, which makes it a very poor candidate for a leukemia-selective drug.

The same thing, for a scientist

TRRAP (Q9Y4A5, 3,859 aa) is a pseudokinase of the PIKK family and the scaffold of the TIP60/NuA4 and SAGA/STAGA acetyltransferase complexes. It was also identified as a component of **DotCom**, the DOT1L complex, alongside SKP1 and beta-catenin and the four MLLT-family KMT2A fusion partners. Its presence there is the main reason the DotCom paper was able to propose a Wnt connection. For this beat the relevant facts are that TRRAP is a co-purifying complex member rather than a mapped KMT2A binder, that no study tests it against a KMT2A fusion protein (bounded 2026-09-19: PubMed `TRRAP[Title/Abstract] AND (MLL OR KMT2A OR leukemia)[Title/Abstract]` returns **4** records - PMIDs 41581705, 20203130, 16714225, 16510874 - of which only the DotCom paper cited here concerns a KMT2A context, and it is a complex-composition result, not a test against the fusion), and that it is among the most pan-essential genes measured anywhere in this project: mean gene effect **-1.49** across 1,208 DepMap lines with **99.5%** of lines depleted and a KMT2A-selectivity of **-0.085**, which is negligible beside a pan-essentiality of that size. Entered so the DotCom composition is complete in the graph and so that the pan-essentiality is on record.

Go deeper
Membership, and the limits of what membership shows

TRRAP appears in DotCom by affinity purification with MudPIT 1. That establishes co-purification with DOT1L. It does not establish a direct contact with DOT1L, with any MLLT protein, or with KMT2A, and the paper does not attempt binary interaction mapping.

TRRAP is also the scaffold of TIP60/NuA4 and of SAGA/STAGA — complexes in which its membership is far better established than in DotCom. A protein that scaffolds several large chromatin complexes is exactly the kind of protein that appears in affinity purifications for reasons that have nothing to do with the bait, and this entry says so rather than treating the DotCom assignment as settled.

Method: affinity purification + MudPIT composition 1. Shown for: wild-type complex in HeLa. Which part of the fusion: none. TRRAP is not a member of the KMT2A::AFF1 interactome.

Pan-essentiality, and what it settles

TRRAP mean gene effect is -1.49 with 99.5% of 1,208 lines depleted 2. Only a handful of genes in this project's data reach that level — HCFC1 (-1.67, 100%), KAT8 (-1.45, 99.5%), SUPT5H (-1.51, 99.4%), SKP1 (-1.28, 99.4%), WDR82 (-2.03, 99.0%).

Its KMT2A-selectivity is -0.085 (mean -1.624 in KMT2A-rearranged lines against -1.539 in other leukemia lines). A difference of that size on top of a baseline of -1.5 is not a therapeutic window; it is a rounding error on a gene that kills everything.

That conclusion holds regardless of whether the DotCom assignment is correct, which is the useful property of a dependency argument: it does not depend on getting the complex-membership question right.

Facts and figures
uniprotQ9Y4A5
gene symbolTRRAP
length AA3859
protein nameTransformation/transcription domain-associated protein
accession resolutionUniProt query gene_exact:TRRAP AND organism_id:9606 AND reviewed:true; primary gene name read back as TRRAP and length 3859 confirmed
interaction evidence classaffinity purification + MudPIT co-purification only
shown for fusionfalse
contact on kmt2a aff1none
druggabilityNot a target. A 3,859-residue pseudokinase scaffold required by 99.5% of cell lines.
alphafold noteAlphaFold DB does not model chains this long (the limit is ~2,700 residues), so no AF-<acc>-F1 entry exists for this protein. A stored identifier of that form was removed on 2026-09-19 after the API returned 404: it had been constructed by rule rather than fetched. KMT2A itself (3,969 aa) is absent from AlphaFold for the same reason.
subnuclear localizationNUCLEOLUS, state-dependently and via MYC - TRRAP is recruited to rDNA after c-Myc/Max association increases on activation of quiescent cells, bringing histone acetylation and Pol I with it (PMID 15723053) [E_q95_trrap_loc2]. Also NUCLEAR FOCI with Ad4BP/SF-1 under PKA activation in human KGN cells, which is a transcription-factor-dependent focus rather than a named body (PMID 14555713) [E_q95_trrap_loc1]. The INVERSE observation is the strongest subnuclear statement available: removing Trrap from mouse ESCs condenses chromatin into distinct foci and uncouples H3K4me2 from H3K27me3 (PMID 23362228) [E_q95_trrap_loc3]. No speckle, no PML body, no Polycomb body has been reported; the whole subnuclear literature is four records.
localization shown for fusionNO - nobody has looked in any KMT2A fusion or any other fusion, in any lineage. Bound: 1 record for the gene clause against a localisation clause AND the fusion clause, which title-checks to 0, and 0 against a subnuclear clause AND the fusion clause, from an operand control of 258 for the gene clause [E_q95_trrap_loc4]. This entry already records shown_for_fusion as a BOOLEAN in the INTERACTOME sense, which is a different question and is left untouched (brief rule 86).
saga module assignment q95ACETYLTRANSFERASE side. TRRAP is the large scaffold of SAGA/TFTC/STAGA and of NuA4/TIP60, alongside KAT2A (tranche 5) and the H3K4me reader SGF29 (tranche 4). It is NOT in the deubiquitinase module, which is ATXN7L3 + USP22 + ENY2 and is amended separately in this same tranche. The two modules have different substrates and different compartment evidence and must not be merged into a single 'SAGA localisation'.
pan essential peers in this beat
WDR82-2.030WDR82: -2.0297HCFC1-1.665HCFC1: -1.6655SUPT5H-1.507SUPT5H: -1.5066KAT8-1.452KAT8: -1.4515SKP1-1.281SKP1: -1.2813
complexes
[
  "DotCom (DOT1L complex)",
  "TIP60/NuA4 acetyltransferase complex",
  "SAGA/STAGA"
]
essentiality
{
  "depmap_common_essential": true,
  "chronos_mean": -1.4932,
  "n_lines": 1208,
  "fraction_lines_depleted": 0.995,
  "chronos_mean_kmt2a_rearranged": -1.6239,
  "chronos_mean_other_leukemia": -1.5386,
  "kmt2a_selectivity_difference": -0.0853,
  "n_kmt2a_rearranged_lines": 11,
  "n_other_leukemia_lines": 43,
  "benchmark_men1_difference": -0.8656
}
pan essential peers in this beat — the numbers behind the chart
[
  {
    "gene": "HCFC1",
    "chronos_mean": -1.6655,
    "frac_depleted": 1
  },
  {
    "gene": "SUPT5H",
    "chronos_mean": -1.5066,
    "frac_depleted": 0.9942
  },
  {
    "gene": "KAT8",
    "chronos_mean": -1.4515,
    "frac_depleted": 0.995
  },
  {
    "gene": "SKP1",
    "chronos_mean": -1.2813,
    "frac_depleted": 0.9942
  },
  {
    "gene": "WDR82",
    "chronos_mean": -2.0297,
    "frac_depleted": 0.9901
  }
]
bounded searches
[
  {
    "query": "TRRAP[Title/Abstract] AND (MLL OR KMT2A OR leukemia)[Title/Abstract]",
    "records": 4,
    "relevant": 1,
    "date": "2026-09-19",
    "source": "PubMed eutils esearch",
    "pmids_returned": [
      "41581705",
      "20203130",
      "16714225",
      "16510874"
    ]
  }
]
localization
{
  "CONSTITUTIVE": "NUCLEUS, but CONDITIONALLY so, and the condition is a partner. UniProt Q9Y4A5's two ECO:0000269 citations are the TRRAP discovery paper and the STAGA purification, neither of which reports a localisation experiment in its abstract [E_q95_trrap_loc1]; a bipartite NLS is mapped at residues 2047-2062. The one imaging study finds TRRAP transfected alone distributed OUTSIDE the nucleus, translocated INTO it in the presence of GCN5, and then co-localised with Ad4BP/SF-1 in nuclear foci on PKA activation, in living human KGN cells by confocal microscopy and FRAP [E_q95_trrap_loc1].",
  "CONDITIONAL_NUCLEOLAR": "nucleolar rDNA, downstream of c-Myc/Max and keyed to the activation of QUIESCENT cells: Myc-Max association with rDNA increases on activation and is followed by TRRAP recruitment, histone acetylation, Pol I recruitment and rDNA transcription [E_q95_trrap_loc2].",
  "how_shown": "confocal imaging plus FRAP on transfected fusions in living human granulosa cells [E_q95_trrap_loc1]; locus occupancy at rDNA in the Myc study [E_q95_trrap_loc2]; nuclear-extract biochemistry for everything UniProt cites.",
  "systems": "human KGN granulosa tumour cells, unspecified human lines for the rDNA work, mouse embryonic stem cells for the state work. NOTHING haematopoietic and nothing leukaemic."
}
cell type
{
  "imaged_in": "human KGN granulosa tumour cells, the only cell in which TRRAP has been microscopically localised [E_q95_trrap_loc1].",
  "functionally_measured_in": "mouse embryonic stem cells and mouse embryonic fibroblasts, where Trrap-Oct4 binding overlap is ESC-specific [E_q95_trrap_loc3]. Nothing haematopoietic.",
  "in_kmt2a_r": "NOTHING positional. This entry's existing position stands: TRRAP is a pan-essential DotCom subunit that every cell needs and no KMT2A cell needs more [E_q95_trrap_loc4]."
}
cell state
{
  "STEM_LIKE_SELF_RENEWAL": "Trrap maintains mouse ESC self-renewal and RESTRICTS differentiation; its loss downregulates Nanog, Oct4 and Sox2 and triggers unscheduled differentiation, while failure to downregulate it PREVENTS differentiation [E_q95_trrap_loc3]. A two-sided switch, which is why a self-renewal result here is not a therapeutic rationale.",
  "QUIESCENT_TO_ACTIVATED": "the nucleolar recruitment is a state transition: Myc-Max rDNA association increases on activation of quiescent cells and TRRAP follows [E_q95_trrap_loc2]. The only state-dependent compartment change reported for this protein.",
  "not_recorded": "no cell-cycle-phase or damage-dependent redistribution; nothing under menin inhibition."
}
localization bounded absence
{
  "date": "2026-09-22",
  "tool": "NCBI E-utilities esearch, db=pubmed",
  "run_by": "Q95",
  "shape": "one [tiab] tag per term (rule 94); cytogenetic terms quoted (rule 95); querytranslation read back and stored (rule 90)",
  "absence_class": "never-measured",
  "queries": {
    "gene_clause_alone": {
      "query": "TRRAP[tiab] OR PAF400[tiab]",
      "count": 258,
      "querytranslation": "\"TRRAP\"[Title/Abstract] OR \"PAF400\"[Title/Abstract]"
    },
    "gene_AND_loc": {
      "query": "(TRRAP[tiab] OR PAF400[tiab]) AND (localization[tiab] OR localisation[tiab] OR subcellular[tiab] OR immunofluorescence[tiab] OR nuclear[tiab] OR cytoplasmic[tiab] OR compartment[tiab])",
      "count": 29,
      "querytranslation": "(\"TRRAP\"[Title/Abstract] OR \"PAF400\"[Title/Abstract]) AND (\"localization\"[Title/Abstract] OR \"localisation\"[Title/Abstract] OR \"subcellular\"[Title/Abstract] OR \"immunofluorescence\"[Title/Abstract] OR \"nuclear\"[Title/Abstract] OR \"cytoplasmic\"[Title/Abstract] OR \"compartment\"[Title/Abstract])"
    },
    "gene_AND_subnuclear": {
      "query": "(TRRAP[tiab] OR PAF400[tiab]) AND (\"nuclear speckle\"[tiab] OR \"nuclear speckles\"[tiab] OR nucleolus[tiab] OR nucleolar[tiab] OR \"PML body\"[tiab] OR \"PML bodies\"[tiab] OR \"nuclear matrix\"[tiab] OR \"Polycomb bodies\"[tiab] OR \"Polycomb body\"[tiab] OR subnuclear[tiab] OR \"nuclear bodies\"[tiab] OR \"nuclear body\"[tiab] OR chromocent*[tiab] OR heterochromat*[tiab])",
      "count": 4,
      "querytranslation": "(\"TRRAP\"[Title/Abstract] OR \"PAF400\"[Title/Abstract]) AND (\"nuclear speckle\"[Title/Abstract] OR \"nuclear speckles\"[Title/Abstract] OR \"nucleolus\"[Title/Abstract] OR \"nucleolar\"[Title/Abstract] OR \"PML body\"[Title/Abstract] OR \"PML bodies\"[Title/Abstract] OR \"nuclear matrix\"[Title/Abstract] OR \"Polycomb bodies\"[Title/Abstract] OR \"Polycomb body\"[Title/Abstract] OR \"subnuclear\"[Title/Abstract] OR \"nuclear bodies\"[Title/Abstract] OR \"nuclear body\"[Title/Abstract] OR \"chromocent*\"[Title/Abstract] OR \"heterochromat*\"[Title/Abstract])"
    },
    "gene_AND_fusion": {
      "query": "(TRRAP[tiab] OR PAF400[tiab]) AND (KMT2A[tiab] OR MLL[tiab] OR \"MLL1\"[tiab] OR \"MLL-AF4\"[tiab] OR \"MLL-AF9\"[tiab] OR \"MLL-ENL\"[tiab] OR \"MLL-AF10\"[tiab] OR \"t(4;11)\"[tiab] OR \"t(11;19)\"[tiab])",
      "count": 3,
      "querytranslation": "(\"TRRAP\"[Title/Abstract] OR \"PAF400\"[Title/Abstract]) AND (\"KMT2A\"[Title/Abstract] OR \"MLL\"[Title/Abstract] OR \"MLL1\"[Title/Abstract] OR \"MLL-AF4\"[Title/Abstract] OR \"MLL-AF9\"[Title/Abstract] OR \"MLL-ENL\"[Title/Abstract] OR \"MLL-AF10\"[Title/Abstract] OR \"t 4 11\"[Title/Abstract] OR \"t 11 19\"[Title/Abstract])"
    },
    "gene_AND_loc_AND_fusion": {
      "query": "(TRRAP[tiab] OR PAF400[tiab]) AND (localization[tiab] OR localisation[tiab] OR subcellular[tiab] OR immunofluorescence[tiab] OR nuclear[tiab] OR cytoplasmic[tiab] OR compartment[tiab]) AND (KMT2A[tiab] OR MLL[tiab] OR \"MLL1\"[tiab] OR \"MLL-AF4\"[tiab] OR \"MLL-AF9\"[tiab] OR \"MLL-ENL\"[tiab] OR \"MLL-AF10\"[tiab] OR \"t(4;11)\"[tiab] OR \"t(11;19)\"[tiab])",
      "count": 1,
      "querytranslation": "(\"TRRAP\"[Title/Abstract] OR \"PAF400\"[Title/Abstract]) AND (\"localization\"[Title/Abstract] OR \"localisation\"[Title/Abstract] OR \"subcellular\"[Title/Abstract] OR \"immunofluorescence\"[Title/Abstract] OR \"nuclear\"[Title/Abstract] OR \"cytoplasmic\"[Title/Abstract] OR \"compartment\"[Title/Abstract]) AND (\"KMT2A\"[Title/Abstract] OR \"MLL\"[Title/Abstract] OR \"MLL1\"[Title/Abstract] OR \"MLL-AF4\"[Title/Abstract] OR \"MLL-AF9\"[Title/Abstract] OR \"MLL-ENL\"[Title/Abstract] OR \"MLL-AF10\"[Title/Abstract] OR \"t 4 11\"[Title/Abstract] OR \"t 11 19\"[Title/Abstract])"
    },
    "gene_AND_subnuclear_AND_fusion": {
      "query": "(TRRAP[tiab] OR PAF400[tiab]) AND (\"nuclear speckle\"[tiab] OR \"nuclear speckles\"[tiab] OR nucleolus[tiab] OR nucleolar[tiab] OR \"PML body\"[tiab] OR \"PML bodies\"[tiab] OR \"nuclear matrix\"[tiab] OR \"Polycomb bodies\"[tiab] OR \"Polycomb body\"[tiab] OR subnuclear[tiab] OR \"nuclear bodies\"[tiab] OR \"nuclear body\"[tiab] OR chromocent*[tiab] OR heterochromat*[tiab]) AND (KMT2A[tiab] OR MLL[tiab] OR \"MLL1\"[tiab] OR \"MLL-AF4\"[tiab] OR \"MLL-AF9\"[tiab] OR \"MLL-ENL\"[tiab] OR \"MLL-AF10\"[tiab] OR \"t(4;11)\"[tiab] OR \"t(11;19)\"[tiab])",
      "count": 0,
      "querytranslation": "(\"TRRAP\"[Title/Abstract] OR \"PAF400\"[Title/Abstract]) AND (\"nuclear speckle\"[Title/Abstract] OR \"nuclear speckles\"[Title/Abstract] OR \"nucleolus\"[Title/Abstract] OR \"nucleolar\"[Title/Abstract] OR \"PML body\"[Title/Abstract] OR \"PML bodies\"[Title/Abstract] OR \"nuclear matrix\"[Title/Abstract] OR \"Polycomb bodies\"[Title/Abstract] OR \"Polycomb body\"[Title/Abstract] OR \"subnuclear\"[Title/Abstract] OR \"nuclear bodies\"[Title/Abstract] OR \"nuclear body\"[Title/Abstract] OR \"chromocent*\"[Title/Abstract] OR \"heterochromat*\"[Title/Abstract]) AND (\"KMT2A\"[Title/Abstract] OR \"MLL\"[Title/Abstract] OR \"MLL1\"[Title/Abstract] OR \"MLL-AF4\"[Title/Abstract] OR \"MLL-AF9\"[Title/Abstract] OR \"MLL-ENL\"[Title/Abstract] OR \"MLL-AF10\"[Title/Abstract] OR \"t 4 11\"[Title/Abstract] OR \"t 11 19\"[Title/Abstract])"
    },
    "trrap_loc": {
      "query": "(TRRAP[tiab] OR PAF400[tiab]) AND (localization[tiab] OR localisation[tiab] OR immunofluorescence[tiab] OR nuclear[tiab])",
      "count": 28,
      "querytranslation": "(\"TRRAP\"[Title/Abstract] OR \"PAF400\"[Title/Abstract]) AND (\"localization\"[Title/Abstract] OR \"localisation\"[Title/Abstract] OR \"immunofluorescence\"[Title/Abstract] OR \"nuclear\"[Title/Abstract])"
    },
    "trrap_saga": {
      "query": "(TRRAP[tiab] OR PAF400[tiab]) AND (SAGA[tiab] OR STAGA[tiab] OR TIP60[tiab] OR NuA4[tiab])",
      "count": 55,
      "querytranslation": "(\"TRRAP\"[Title/Abstract] OR \"PAF400\"[Title/Abstract]) AND (\"SAGA\"[Title/Abstract] OR \"STAGA\"[Title/Abstract] OR \"TIP60\"[Title/Abstract] OR \"NuA4\"[Title/Abstract])"
    }
  },
  "title_check": "gene_AND_subnuclear, 4 records: 23362228 (Trrap ESC self-renewal, heterochromatization), 15723053 (c-Myc rDNA, TRRAP recruitment), 14555713 (SF-1/GCN5/TRRAP confocal in living KGN cells), 15020470 (Drosophila 2R heterochromatin genetics, off topic) - 3 of 4 on topic. gene_AND_loc_AND_fusion, 1 record, 16510874, OFF TOPIC (APC/beta-catenin, MLL as a family name).",
  "rule_64_complex_form": "TRRAP or PAF400 against SAGA, STAGA, TIP60 or NuA4 returns 55 records against 4 for the subnuclear clause, and the complex form is what reaches the positional literature."
}
How this could bite us back
  • TRRAP is required by essentially every cell line tested; any agent against it would be a general cytotoxic with no fusion selectivity.
  • Because TRRAP scaffolds several acetyltransferase complexes, partial inhibition would perturb acetylation broadly and unpredictably rather than acting on H3K79 biology.
Still open
  1. Is TRRAP a genuine DotCom subunit or a carry-over from its TIP60/SAGA scaffolding roles? Re-purifying DotCom with a TRRAP-depleted background would answer it.
  2. Does DOT1L depend on TRRAP for anything measurable in a KMT2A-rearranged cell, or is the association inert there?
Every source behind this entry (6)
  1. E1moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper

    TRRAP is a component of the multisubunit Dot1 complex DotCom, together with DOT1L, ENL, AF9/MLLT3, AF17/MLLT6, AF10/MLLT10, Skp1 and beta-catenin.

    Linking H3K79 trimethylation to Wnt signaling through a novel Dot1-containing complex (DotCom). · Mohan M, Herz HM, Takahashi YH, Lin C, Lai KC, Zhang Y, Washburn MP, Florens L, Shilatifard A · Genes & Development 2010
    PMID 20203130DOI
    What this evidence cannot show

    Abstract read in full; not full text. Co-purification only, with no binary interaction mapping. TRRAP is the scaffold of TIP60/NuA4 and SAGA/STAGA and is a frequent, abundant presence in chromatin affinity purifications, so its assignment to DotCom carries more risk of being an association artefact than the MLLT subunits do. No leukemia model and no fusion protein anywhere in the study.

    Evidence that argues against this (1)
    • TRRAP's DotCom membership is a MudPIT co-purification call on a 3,859-residue scaffold that is also the backbone of TIP60/NuA4 and SAGA/STAGA - i.e. the single most likely protein in the preparation to be a shared rather than a dedicated subunit. van Nuland et al. show what it takes to make that call properly: label-free quantitative mass spectrometry on the human SET1/MLL complexes resolved 'known and novel, unique and shared interactors', determined their stoichiometry and distribution across complexes, and reassigned a long-accepted core COMPASS subunit (DPY30) as a genuine NURF subunit as well. The DotCom composition was never quantified that way. This entry's own first open question - whether TRRAP is a genuine DotCom subunit or a carry-over - now has a named method attached to it. Read: abstract in full, not full text. van Nuland R et al. 2013
  2. E2strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.dataset

    TRRAP has DepMap mean gene effect -1.4932 across 1,208 lines with 99.5% of lines depleted, mean -1.6239 in 11 KMT2A-rearranged leukemia lines against -1.5386 in 43 other leukemia lines (difference -0.085); MEN1 in the same lines is -0.866 with an all-lines mean of only -0.363.

    DepMap CRISPR (Chronos) gene effect via the Open Targets Platform GraphQL API, with KMT2A-rearrangement status from Cellosaurus; per-gene recomputation for this beat · Broad Institute DepMap; Cellosaurus; Open Targets Platform; analysis run by this project · Database and derived analysis 2026
    What this evidence cannot show

    DepMap release version not stated by the API. A gene depleted in 99.5% of lines has almost no dependency variance, so any difference computed on it is dominated by measurement noise and should not be interpreted directionally.

    Evidence that argues against this (1)
    • The entry concludes that a -0.085 selectivity is 'negligible beside a pan-essentiality of that size', which is right about the measurement and should not be read as a statement about targetability. Valerio et al. show MOF/KAT8, also broadly required and with no KMT2A selectivity in this graph's scan, is nonetheless required for MLL-AF9 leukemia maintenance in vivo, that the requirement is catalytic, and that a MYST HAT inhibitor is antiproliferative in human KMT2A-rearranged lines - with the full text adding that non-KMT2A lines are sensitive too and that Hoxa9/Meis1 are unaffected. Pan-essentiality compresses the measurable difference to the floor; it does not establish that a pan-essential complex member is therapeutically inert, only that CRISPR knockout cannot tell you. Read: FULL TEXT via PMC5501293. Valerio DG et al. 2017
  3. E_q95_trrap_loc1established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database

    Both of UniProt Q9Y4A5's experimental citations for TRRAP's 'Nucleus' are papers whose abstracts describe NO localisation experiment: PubMed 9708738 is the TRRAP discovery paper, which isolates a 434 kDa c-Myc N-terminus-binding protein with ATM/PI3-kinase homology and shows that transdominant mutants and antisense RNA block c-Myc- and E1A-mediated transformation; PubMed 11564863 is the purification and characterisation of the human STAGA complex, a HeLa-cell biochemistry paper. The record does however carry a mapped bipartite nuclear localization signal at residues 2047-2062, which is more than the MEN1 record in brief rule 91 has.

    What this evidence cannot show

    A statement about the database record. Both papers are genuine TRRAP papers and a 434 kDa transcription-coactivator scaffold purified from HeLa nuclear extract is obviously nuclear - the defect is that the compartment is INFERRED FROM BIOCHEMISTRY, which is the same shape as the AFF4 case in brief rule 91, where a P-TEFb affinity-purification paper whose abstract describes no localisation experiment is UniProt's citation for a compartment. Brief rule 80 applies: a colocalisation panel could exist in either full text.

    Evidence that argues against this (1)
    • AND THE PAPER THAT DOES IMAGE TRRAP REPORTS THE OPPOSITE OF A SIMPLE NUCLEAR CALL, WHICH IS WHY THE MISSING CITATION MATTERS RATHER THAN BEING A TECHNICALITY. In living human KGN granulosa cells by laser confocal microscopy and FRAP, GCN5 and TRRAP transfected separately were 'unexpectedly diffuse INSIDE and OUTSIDE the nucleus respectively' - that is, TRRAP alone distributed outside the nucleus - and TRRAP was translocated INTO the nucleus in the presence of GCN5, after which both colocalised with Ad4BP/SF-1 in nuclear foci when PKA was activated. So TRRAP's nuclear residence is partner-dependent, and a record that says 'Nucleus' on two biochemistry papers conceals a conditional compartment that one imaging paper measured. This is the THIRD complex-dependent nuclear residence in this localisation series - SGF29 in fission yeast needs sgf73+, Paf1C's subnuclear position depends on Pol II attachment, and TRRAP needs GCN5 - which makes it a pattern rather than a curiosity. Fan W et al. 2004
  4. E_q95_trrap_loc2strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

    TRRAP has a state-dependent NUCLEOLAR address and it is reached through MYC: c-Myc and Max interact in nucleoli and are associated with ribosomal DNA, the association increases upon ACTIVATION OF QUIESCENT CELLS, and it is followed by recruitment of the Myc cofactor TRRAP, enhanced histone acetylation, recruitment of RNA polymerase I and activation of rDNA transcription - so TRRAP's arrival at nucleolar rDNA is downstream of Myc and keyed to a proliferative state transition rather than constitutive.

    c-Myc associates with ribosomal DNA and activates RNA polymerase I transcription. · Arabi A, Wu S, Ridderstråle K, Bierhoff H, Shiue C, Fatyol K, Fahlén S, Hydbring P, Söderberg O, Grummt I, Larsson LG, Wright AP · Nat Cell Biol 2005
    PMID 15723053DOI
    What this evidence cannot show

    TRRAP's recruitment is one step in a described sequence and the paper's subject is c-Myc; the abstract does not state which assay placed TRRAP at rDNA (chromatin immunoprecipitation is the likely one) or in which cell line, so this is occupancy at a locus inside a compartment rather than an imaged compartment. It is nonetheless the only nucleolar statement about TRRAP in the reachable literature: TRRAP or PAF400 against a subnuclear clause returns 4 records in total.

    Evidence that argues against this (1)
    • THIS IS THE MOST CONSEQUENTIAL THING IN THIS ENTRY AND IT CUTS BOTH WAYS FOR THE PROJECT. For: the single most enriched complex in the MLL-fusion interactome by this project's own analysis is nucleolar/ribosome biogenesis - 15 of 26 members, q = 8.4e-13 against the proteome and 2.7e-05 against a nuclear background - so a MYC-dependent route that delivers an acetyltransferase scaffold to rDNA is a candidate mechanism for that enrichment, and MYC is central in this disease. Against: TRRAP is DepMap common-essential and every cell needs rRNA, so a nucleolar TRRAP pool is expected in any proliferating cell and explains nothing specific to a KMT2A fusion. The discriminating measurement is not whether TRRAP is nucleolar but whether the fusion changes the Myc-dependent step - and nobody has run a TRRAP ChIP at rDNA in a KMT2A-rearranged cell, quiescent or cycling. Martinez E et al. 2001
  5. E_q95_trrap_loc3strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

    TRRAP's cell type and cell state are measured in mouse embryonic stem cells and the result is a SUBNUCLEAR one as well as a state one: conditional deletion of Trrap in mouse ESCs triggers unscheduled differentiation associated with loss of histone acetylation, CONDENSATION OF CHROMATIN INTO DISTINCT FOCI (heterochromatization) and uncoupling of H3K4 dimethylation from H3K27 trimethylation; stemness genes Nanog, Oct4 and Sox2 are downregulated; Trrap and Oct4 binding overlap significantly in ESCs but not in differentiated fibroblasts; and failure to downregulate Trrap PREVENTS differentiation.

    Histone acetyltransferase cofactor Trrap maintains self-renewal and restricts differentiation of embryonic stem cells. · Sawan C, Hernandez-Vargas H, Murr R, Lopez F, Vaissière T, Ghantous AY, Cuenin C, Imbert J, Wang ZQ, Ren B, Herceg Z · Stem Cells 2013
    PMID 23362228DOI
    What this evidence cannot show

    Mouse embryonic stem cells, not haematopoietic and not leukaemic - brief rule 73 applies and the claim names the system. The heterochromatization is a consequence of losing TRRAP rather than a place TRRAP sits, so it belongs in cell state and in the subnuclear field only as an inverse observation: removing this protein reorganises the nucleus.

    Evidence that argues against this (1)
    • THE BIDIRECTIONALITY IS THE OBJECTION AND IT MATTERS FOR ANY THERAPEUTIC READING. The same paper reports that Trrap loss forces differentiation AND that failure to downregulate Trrap PREVENTS it - so TRRAP level is a two-sided switch, and lowering it in a leukaemic stem cell could as easily be predicted to force differentiation (desirable) as to be lethal to every dividing cell (not selective). This entry's existing position is the second reading: TRRAP is a 3,859-residue pan-essential DotCom and SAGA/NuA4 scaffold that every cell needs and no KMT2A cell needs more. A stem-cell self-renewal result is exactly the kind of finding that gets quoted as a therapeutic rationale without the pan-essentiality beside it, and the two have to travel together. Fan W et al. 2004
  6. E_q95_trrap_loc4strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.database

    Bounded 2026-09-22: no TRRAP compartment has been measured in any KMT2A-fusion cell, and TRRAP's subnuclear literature is four records. The gene clause over TRRAP and PAF400 returns 258 records and intersects the nine-term KMT2A/MLL fusion clause at 3; with a localisation clause it returns 29 and with the fusion clause added 1, which title-checks to 0 (the single hit is an APC/beta-catenin H3K4-methylation paper where MLL is a family name); with a subnuclear clause it returns 4 and with the fusion clause added 0. The SAGA/STAGA/TIP60/NuA4 complex-form query returns 55, and it is what reaches this protein's real positional literature.

    What this evidence cannot show

    Titles and abstracts only; supporting figures not searched (rule 80). Rule 64 was applied and is decisive here: the complex form returns 55 records against 4 for the subnuclear clause, and the two papers that actually image or place TRRAP - the SF-1/GCN5 confocal study and the c-Myc rDNA study - carry neither TRRAP nor PAF400 in a position that a subnuclear query reaches.

    Evidence that argues against this (1)
    • THE MORE USEFUL BOUND IS THE MODULE ONE, AND IT IS WHERE THIS TRANCHE HAD TO BE CAREFUL. TRRAP belongs to the ACETYLTRANSFERASE side of SAGA/TFTC/STAGA and to NuA4/TIP60 - it is the scaffold, not a catalytic or reader subunit - whereas ATXN7L3, amended in this same tranche, belongs to the DEUBIQUITINASE module with USP22 and ENY2. This graph now holds KAT2A (tranche 5), SGF29 (tranche 4) and TRRAP on the HAT side and ATXN7L3 on the DUB side, and the two modules have different substrates, different partners and, as it turns out, different compartment evidence: the HAT-side proteins have complex-dependent nuclear residence measurements and the DUB-side adaptor has a paralogue-resolved one. Treating 'SAGA localisation' as one fact would erase that. Zhao Y et al. 2008
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