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Proteinmoderate confidence 3 of 5: One strong study, or several smaller consistent ones.Q-fa-replication

UBE2T — E2; rank 33 of 8,269 for KMT2A-selective dependency, and no KMT2A literature at all

also called UBE2T · FANCT · HSPC150 · Q9NPD8

UBE2T is part of a cellular repair crew that fixes DNA when the copying machinery gets stuck. A screen run by this project found that leukaemia cells carrying the KMT2A fusion need it more than other leukaemia cells do — and nobody has ever published a paper on this gene in KMT2A leukaemia, so the finding is genuinely new and genuinely unconfirmed.

The same thing, for a scientist

UBE2T (UniProt Q9NPD8, 197 aa, primary gene name asserted against the accession) sits in the E2 — the ubiquitin-conjugating enzyme that hands ubiquitin to FANCL; the only enzyme in the set with a catalytic pocket of its own. It entered this graph through a DepMap sweep in which the 26-gene FA/BRCA annotation beats a permutation null at p = 5e-05, UBE2T ranking 33 of 8,269 by raw effect (d = -0.24) [E2]. Re-testing here: the depletion is present in BOTH lineage halves (-0.2434 myeloid, -0.5869 lymphoid) and stronger in the lymphoid one; it survives a line-label permutation that preserves subunit correlations (p = 0.0008); and UBE2T is not pan-essential (mean Chronos -0.2283 across all screened lines) [E3][E4]. Three things cut against it. Non-KMT2A B-ALL lines show about half the same effect, so a large part of this is B-lymphoid lineage rather than KMT2A rearrangement [E3]. The obligate FA core subunits do NOT move together, which is hard to reconcile with a canonical pathway dependency. And Fanconi anaemia patients, who have no FA pathway at all, nonetheless develop KMT2A-rearranged leukaemia [E7].

Go deeper
What the protein does, and which part of the pathway it sits in

Module: E2 — the ubiquitin-conjugating enzyme that hands ubiquitin to FANCL; the only enzyme in the set with a catalytic pocket of its own.

UniProt describes UBE2T as the specific E2 ubiquitin-conjugating enzyme for the Fanconi anemia complex, associating with FANCL and catalysing monoubiquitination of FANCD2 1.

Why the module matters for reading the DepMap result: the FA core complex is an obligate multi-subunit ubiquitin ligase whose only well-established job is to monoubiquitinate the FANCD2-FANCI (ID2) heterodimer. If the dependency seen here were the canonical pathway working as a unit, every obligate core subunit and the ID2 substrate should move together. They do not — see mech-fa-core-complex-heterogeneity-kmt2a. That is the single most important caveat on this entry and it is not a small one.

How this gene entered the graph, and the numbers

UBE2T was not found in the literature. It was found by a scan, and then by a pathway permutation over a gene set fixed before any result was read 2.

statisticvalue
rank by raw effect, 8,269-gene sweep33
rank by scaled z65
d (Chronos difference), whole index arm-0.24
d, myeloid half-0.2434
d, lymphoid half-0.5869
z, myeloid half-0.805
z, lymphoid half-1.942
pan-cancer Chronos, all screened lines-0.2283
fraction of all lines below -0.59.1%
line-label permutation p0.0008

Two of those rows carry most of the weight. The lineage split 3 is the one the project asked for, and the answer is not the one the myeloid-artefact worry predicted: this gene is depleted MORE in the four B-lineage lines than in the seven myeloid ones. The line-label permutation 3 is the answer to the complex-correlation objection: redrawing which lines are the index arm, with the gene set held fixed and the 7-myeloid/4-lymphoid composition reproduced, preserves every correlation between subunits, and the observed depletion still sits at p = 0.0008.

And UBE2T is not pan-essential 4, which is the filter that removed most of the earlier scan's contaminants.

The published literature, and a counted absence

On UBE2T in KMT2A-rearranged leukaemia there is nothing. 5 The exact query and the title-checked count are in the evidence item; aliases searched were UBE2T, FANCT, HSPC150.

On UBE2T in leukaemia at all, 3 records. 6

And the counter-direction. Human FA patients develop KMT2A-rearranged leukaemia 7. A cell that has lost the FA pathway entirely can still acquire a KMT2A fusion and expand into a clinical leukaemia, which rules out the strongest reading of the DepMap result — that KMT2A-rearranged cells REQUIRE this pathway — and leaves only the quantitative one.

Facts and figures
uniprotQ9NPD8
length AA197
uniprot resolutiongene_exact:UBE2T AND organism_id:9606 AND reviewed:true; primary gene name read back as UBE2T; length 197 aa checked against the entry
fa moduleE2 — the ubiquitin-conjugating enzyme that hands ubiquitin to FANCL; the only enzyme in the set with a catalytic pocket of its own
cell context evidence classrequired_in (human HSC, by germline genetics and somatic reversion; and KMT2A-rearranged B-lineage lines, by CRISPR with a lineage split). NOT maintains_a_state, and no cell-type-restricted expression is claimed - UBE2T is broadly expressed and the FA phenotype is tissue-selective because the marrow is where the demand is highest.
cell context shown for fusionNO for everything published, YES only for this project's own unpublished scan. Re-measured 2026-09-21: (UBE2T[tiab] OR FANCT[tiab]) AND (KMT2A[tiab] OR MLL[tiab] OR "mixed-lineage leukemia"[tiab]) returns 0 records, with operands of 213 and 8,160 respectively - a genuine empty intersection of two non-trivial sets. Zero in titles and abstracts; supporting figures not searched. The cell-type evidence added here is FANCONI ANAEMIA evidence, in normal human haematopoiesis, and it bears on the index disease only through the shared cell type.
cell context readingThe two halves fit together better than either does alone. Human genetics says UBE2T is limiting in the haematopoietic stem cell; this project's screen says the requirement is strongest in KMT2A-rearranged B-lineage lines. Neither is a fusion-context experiment, and the honest summary is that the cell type is established and the fusion context is not.
subnuclear localizationchromatin, damage-induced, and nothing finer. UBE2T and FANCD2 access the chromatin fraction independently of the FA core complex, and FANCD2 monoubiquitination is set by formation of an active E2/E3 holoenzyme on chromatin rather than by complex assembly (PMID 17938197). No subnuclear body has ever been assigned to UBE2T - this is unpublished, not not-applicable: UBE2T is a nuclear protein and the question is answerable, nobody has asked it.
shown for fusionNO, and the zero is upstream of localisation. Measured 2026-09-21 with NCBI esearch: (UBE2T[tiab] OR FANCT[tiab] OR HSPC150[tiab]) AND (MLL[tiab] OR KMT2A[tiab] OR MLL-AF4[tiab] OR MLL-AF9[tiab] OR mixed lineage leukemia[tiab]) AND (localiz*[tiab] OR localis*[tiab] OR subcellular[tiab] OR nuclear body[tiab] OR nuclear bodies[tiab] OR speckle*[tiab] OR condensat*[tiab] OR nucleolar[tiab] OR immunofluorescence[tiab] OR compartment*[tiab]) returns 0. Operands: gene clause 214 records, gene AND fusion clause 0 - so there is no UBE2T-and-KMT2A literature at all, and the localisation term removes nothing because there was nothing left to remove. This matches the entry's existing cell-context finding. Positive control through the identical query shape, substituting (MLLT1[tiab] OR ENL[tiab]), returns 23. Zero in titles and abstracts; supporting figures not searched (brief rule 80).
depmap kmt2a selectivity
z_lymphoid_half-1.942z_lymphoid_half: -1.942z_myeloid_half-0.805z_myeloid_half: -0.805z_index_vs_other_leukaemia-0.796z_index_vs_other_leukaemia: -0.796d_lymphoid_half-0.587d_lymphoid_half: -0.5869d_myeloid_half-0.243d_myeloid_half: -0.2434d_index_vs_other_leukaemia-0.240d_index_vs_other_leukaemia: -0.24line_label_permutation_p0.001line_label_permutation_p: 0.0008n_index_lines11.0n_index_lines: 11rank_by_raw_effect_of_826933.0rank_by_raw_effect_of_8269: 33n_comparator_leukaemia_li…43.0n_comparator_leukaemia_lines: 43rank_by_z_of_826965.0rank_by_z_of_8269: 65
essentiality
{
  "depmap_common_essential": false,
  "chronos_mean": -0.2283,
  "frac_lines_below_minus_0_5": 0.091
}
depmap kmt2a selectivity — the numbers behind the chart
{
  "rank_by_raw_effect_of_8269": 33,
  "rank_by_z_of_8269": 65,
  "d_index_vs_other_leukaemia": -0.24,
  "z_index_vs_other_leukaemia": -0.796,
  "d_myeloid_half": -0.2434,
  "d_lymphoid_half": -0.5869,
  "z_myeloid_half": -0.805,
  "z_lymphoid_half": -1.942,
  "line_label_permutation_p": 0.0008,
  "n_index_lines": 11,
  "n_comparator_leukaemia_lines": 43
}
literature
{
  "kmt2a_records_raw": 0,
  "kmt2a_records_title_checked": 0,
  "leukaemia_records": 3,
  "aliases_searched": [
    "UBE2T",
    "FANCT",
    "HSPC150"
  ],
  "kmt2a_query": "(UBE2T[tiab] OR FANCT[tiab]) AND (KMT2A[tiab] OR MLL[tiab] OR \"mixed-lineage leukemia\"[tiab])",
  "leukaemia_query": "(UBE2T[tiab] OR FANCT[tiab]) AND (leukemia[tiab] OR leukaemia[tiab])"
}
cell type
{
  "required_in_humans": "The haematopoietic stem cell, established by human germline genetics rather than by any leukaemia experiment. Biallelic UBE2T mutations cause Fanconi anaemia - complementation group FA-T - a disorder characterised by genome instability, cancer susceptibility, progressive BONE MARROW FAILURE and developmental abnormalities. In one FA-T patient carrying a paternal deletion and a maternal duplication of exons 2-6, the maternal allele spontaneously REVERTED to wild type by monoallelic recombination at the duplicated AluY repeat IN THE PATIENT'S HAEMATOPOIETIC STEM CELLS, thereby preventing bone marrow failure.",
  "why_that_reversion_matters": "Somatic reversion in HSCs that rescues the marrow is about as direct a demonstration as human genetics offers that the cell type in which UBE2T function is limiting IS the haematopoietic stem cell. It is a natural experiment with an internal control - the same patient, the same gene, two alleles, one corrected.",
  "required_in_leukaemia": "This project's own genome-scale screen, lineage-split as the standing rule requires: UBE2T is more required in the B-LINEAGE half of the KMT2A-rearranged arm (d -0.587, z -1.942) than in the myeloid half (d -0.243, z -0.805), with line-label permutation p = 0.0008, rank 33 of 8,269 on raw effect and 65 by z. The index lineage is the one where the signal is strongest, which is the right direction and is unconfirmed by any published work.",
  "how_shown": "human germline genetics with cellular complementation (FA-T); somatic reversion analysis in patient HSCs; DepMap Chronos with lineage split and line-label permutation",
  "nodes": [
    "cell-type-hsc-bone-marrow"
  ]
}
cell state
{
  "maintains_state": "not established. No experiment shows UBE2T maintaining any cell identity. The FA phenotype is loss of genome-stability capacity leading to progressive marrow failure - a functional collapse, not an identity change - and the DepMap signal is a fitness readout. Recorded as a bounded absence rather than inferred.",
  "nodes": []
}
localization
{
  "subcellular": "Nucleus, and nothing else is annotated. UniProt Q9NPD8 records a single location, Nucleus, at ECO:0000269. There is no published image of UBE2T in a haematopoietic cell of any kind.",
  "subnuclear": "CHROMATIN, and specifically the DNA-damage-induced chromatin fraction - reached independently of the Fanconi anaemia core complex. No nuclear body, speckle, nucleolar or condensate assignment exists for UBE2T anywhere in the literature; the only spatial statement that has ever been made about it is a fractionation result. That makes UBE2T the clean case of the chromatin-bound versus soluble axis this graph already records as the one localisation readout that keeps a size dimension.",
  "how_shown": "chromatin fractionation with and without DNA damage, plus separation of core-complex assembly from E3 activity (PMID 17938197); in vivo automonoubiquitination and FANCL binding (PMID 16916645); UniProt Q9NPD8 SUBCELLULAR LOCATION comment.",
  "systems": "cultured human and DT40 cells of the Fanconi anaemia field; no leukaemia system, no KMT2A-rearranged arm and no primary haematopoietic material in any localisation source",
  "node": "localization-chromatin-bound-versus-soluble-fraction-kmt2a"
}
How this could bite us back
  • The FA pathway is a tumour suppressor pathway. Inhibiting it in a leukaemia patient would be expected to raise, not lower, the mutation rate in surviving cells and in normal haematopoiesis — the exact phenotype Fanconi anaemia patients have.
  • Fanconi anaemia is a bone-marrow-failure syndrome. A systemic inhibitor of this pathway carries a named, well-characterised on-target toxicity in the tissue the disease lives in.
  • Children cured of leukaemia live for decades. A drug that disables interstrand cross-link repair sits badly beside the secondary-malignancy risk that already follows topoisomerase-II-directed therapy for KMT2A-rearranged disease.
  • UBE2T has no reported small-molecule ligand, and only UBE2T among the eight carries a catalytic site of the kind ligand discovery usually needs.
  • A quarter-Chronos difference is a narrow therapeutic window even if it is real.
  • ESSENTIAL-FUNCTION TOXICITY — UBE2T is the FA-T gene and biallelic loss causes progressive bone marrow failure in children. A UBE2T inhibitor is therefore an agent whose complete-loss phenotype in humans is the exact organ toxicity that limits leukaemia therapy, in the exact cell type being treated. The counterargument is dose and duration rather than mechanism, and the somatic-reversion case shows how strongly the marrow selects for restored function.
  • COMPENSATION — The requirement identified by this project's screen sits in the Fanconi/BRCA interstrand-crosslink pathway, which is redundant with other double-strand-break repair routes. The graph's companion entry already records that the Fanconi dependency in AML can be created by transcriptional silencing of ALDH2, i.e. by aldehyde load rather than by fusion status - so a cell that lowers its endogenous aldehyde burden could compensate without touching the pathway at all.
Still open
  1. Is UBE2T depleted in KMT2A-rearranged cells because of replication stress at transcribed loci, because of endogenous aldehyde damage as the ALDH2 work in AML argues, or for a third reason?
  2. Does UBE2T knockout cause measurable fork slowing or R-loop accumulation in a KMT2A-rearranged line, or only loss of viability?
  3. Is the B-lymphoid component of this signal a property of B-ALL biology, or of the nine non-KMT2A B-ALL lines that happen to be in DepMap?
  4. Do primary KMT2A-rearranged blasts or patient-derived xenografts show the same UBE2T requirement, or is it a property of decades-passaged lines?
  5. This project's scan places UBE2T's strongest requirement in the B-lineage half of the KMT2A-rearranged arm while human genetics places the limiting cell type at the haematopoietic stem cell. Are these the same requirement seen at two developmental stages, or two different ones? Testing UBE2T dependency in a KMT2A::AFF1 B-ALL line against a matched non-KMT2A B-ALL line is the direct experiment and nobody has run it.
  6. The therapeutic window question for UBE2T is set by Fanconi anaemia: biallelic loss causes progressive marrow failure in humans. Does heterozygous or partial UBE2T reduction produce any marrow phenotype, and is there a dose at which KMT2A-rearranged B-lineage cells lose fitness before normal HSCs do? FA-T carrier parents are an existing, unexamined natural cohort.
  7. UBE2T ranked 33 of 8,269 on this project's KMT2A-selectivity scan and has no KMT2A literature whatever, including no localisation. Does UBE2T load onto chromatin in an index KMT2A::AFF1 line at baseline, without exogenous damage? If it does, the dependency is a replication-stress phenotype rather than a repair-on-demand one, and that distinction sets whether a UBE2T inhibitor would need a damaging partner drug.
  8. Automonoubiquitination inactivates UBE2T. Is the chromatin-bound pool in a KMT2A-rearranged cell enriched for the active or the self-inactivated form? No published assay separates them in any cell type.
Every source behind this entry (11)
  1. E1established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database

    UBE2T is UniProt Q9NPD8, 197 aa, and the accession's PRIMARY gene name reads back as UBE2T. UniProt describes UBE2T as the specific E2 ubiquitin-conjugating enzyme for the Fanconi anemia complex, associating with FANCL and catalysing monoubiquitination of FANCD2.

    UniProtKB entry Q9NPD8 · UniProtKB/Swiss-Prot 2026
    What this evidence cannot show

    A database record, not an experiment. The accession was resolved by a gene_exact query and then read back: gene_exact matches SYNONYMS, so the primary gene name and the sequence length were both checked against the entry rather than assumed.

    Evidence that argues against this (1)
    • UniProt function text for the FA core subunits is hedged ('may operate in', 'may be implicated in') and largely predates the structural work on the complex; it should not be read as a precise mechanistic claim. UniProtKB/Swiss-Prot 2026
  2. E2moderate confidence 3 of 5: One strong study, or several smaller consistent ones.dataset

    In the project's own genome-scale sweep, UBE2T ranks 33 of 8,269 by raw effect (d = -0.24) and 65 by the scaled z (-0.796), and the 26-gene FA/BRCA set as a whole beats its permutation null at p = 5e-05 on both statistics.

    Effect-size versus z re-ranking of the genome-scale lineage-consistency sweep, with a permutation test of the Fanconi/FA-BRCA pathway · Oncofusion knowledge graph, analyses/effect-size-vs-z-reranking; DepMap Chronos via Open Targets 2026
    What this evidence cannot show

    DepMap CRISPR gene effect in 11 KMT2A-rearranged leukaemia lines against 43 other leukaemia lines. Eleven immortalised lines, none infant-derived, lineage assigned from DepMap free-text disease strings. A rank is not an effect: d here is a Chronos difference of roughly a quarter to a half, which is real but far from the -0.86 of MEN1.

    Evidence that argues against this (1)
  3. E3moderate confidence 3 of 5: One strong study, or several smaller consistent ones.dataset

    Splitting the index arm, UBE2T is depleted in BOTH halves (d = -0.2434 myeloid, -0.5869 lymphoid; z = -0.805 and -1.942), and the LYMPHOID half is the stronger one. A line-label permutation that holds the gene set fixed and redraws the index arm as 7 myeloid + 4 lymphoid leukaemia lines gives p = 0.0008 for UBE2T, and p = 0.0002 for the eight-gene headline set.

    What this evidence cannot show

    The lymphoid half is four cell lines. The line-label permutation is the right null for correlated subunits because it preserves every gene-gene correlation, but it cannot tell a KMT2A effect from anything else those eleven particular lines share.

    Evidence that argues against this (1)
  4. E4moderate confidence 3 of 5: One strong study, or several smaller consistent ones.dataset

    UBE2T is not pan-essential: mean Chronos across every screened cell line is -0.2283, and only 9.1% of lines fall below -0.5. For contrast ACTB is -0.815 with 72.1%.

    What this evidence cannot show

    Computed from the Open Targets slice of DepMap, which does not state its release version. 'Not pan-essential' is a weaker statement than 'selective': a gene can be non-essential everywhere and still not be selectively required in KMT2A-rearranged cells.

    Evidence that argues against this (1)
  5. E5strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.database

    There is no published literature on UBE2T in KMT2A-rearranged leukaemia. A PubMed title/abstract search including the retired and alternative symbols UBE2T, FANCT, HSPC150 against KMT2A, MLL and 'mixed-lineage leukemia' returns 0 records, of which 0 are substantive after title-checking every hit.

    What this evidence cannot show

    A counted absence is only as good as its symbol set, and short or word-like aliases inflate counts rather than shrink them, so every hit was title-checked and the checked number is the one reported. Title/abstract search misses work buried in supplementary tables and in screens that name a pathway rather than a gene.

    Evidence that argues against this (1)
    • The pathway is not unstudied even where the gene is: a Hoxa-dependency transcriptome in MLL-rearranged mouse leukaemia returns an FA-pathway-enriched signature, which no gene-symbol query would find. Kettyle LM et al. 2019
  6. E6strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

    UBE2T in leukaemia more broadly: 3 PubMed records for the symbol and its aliases against leukaemia or leukaemia. A domain-focused CRISPR screen across cancer cell lines identified UBE2T and FANCL as selective dependencies in AML, and attributed them to synthetic lethality with methylation silencing of ALDH2 rather than to any fusion. This is independent experimental confirmation that an FA dependency exists in acute leukaemia.

    PMID 33893150DOI
    What this evidence cannot show

    The comparator is other cancer lineages, not other leukaemias, so this establishes an AML dependency and not a KMT2A one, and the lines are again immortalised cultures.

    Evidence that argues against this (1)
    • It supplies a complete competing mechanism - endogenous aldehyde genotoxicity with ALDH2 silenced - that has nothing to do with transcription-replication conflict, and it predicts the dependency tracks ALDH2 methylation rather than KMT2A status. Notably this project's own non-KMT2A AML arm shows NO FA depletion (headline-eight mean d +0.095), so whatever ALDH2 silencing does, it does not reproduce as an AML-versus-other-leukaemia contrast here. Yang Z et al. 2021
  7. E7moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper

    Human Fanconi anaemia patients, who are biallelically null for an FA gene, do develop KMT2A-rearranged leukaemia — a documented case of therapy-related AML carrying MLL-CBP t(11;16) arising in a child with Fanconi anaemia after topoisomerase-II-directed chemotherapy for ALL.

    PMID 10679915
    What this evidence cannot show

    A single 2000 case report, and the FA complementation group is not stated in the abstract, so which FA gene was lost is not established from this record. Therapy-related leukaemia in an FA background is also a special case.

    Evidence that argues against this (1)
    • This is the sharpest argument against reading the DepMap signal as an absolute requirement: a KMT2A-rearranged clone arose and expanded in a host with a disabled FA pathway. It does not exclude a quantitative dependency, and the DepMap effect sizes are quantitative, not absolute. Quentin S et al. 2011
  8. E8established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paper

    Biallelic UBE2T mutations cause Fanconi anaemia, a disorder characterised by genome instability, increased cancer susceptibility, progressive bone marrow failure and developmental abnormalities: two unrelated affected individuals each carried biallelic UBE2T mutations producing a defective protein with the same p.Gln2Glu missense alteration, which abolished FANCD2 monoubiquitination and interaction with FANCL, defining the complementation group FA-T.

    Mutations in the gene encoding the E2 conjugating enzyme UBE2T cause Fanconi anemia. · Hira A, Yoshida K, Sato K, Okuno Y, Shiraishi Y, Chiba K, Tanaka H, Miyano S, Shimamoto A, Tahara H, Ito E, Kojima S, Kurumizaka H, Ogawa S, Takata M, Yabe H, Yabe M · Am J Hum Genet 2015
    PMID 26046368DOI
    What this evidence cannot show

    Two unrelated patients - a case-report-class genetic finding, subsequently confirmed by independent groups. Human germline biology, not leukaemia and not a KMT2A-rearranged system. Lifelong biallelic loss from conception is not the exposure a UBE2T inhibitor would produce in a child, and the standing scope caution on constitutional genetics applies. Read: abstract only.

    Evidence that argues against this (1)
    • The cell-type conclusion should not rest on the clinical phenotype alone, because bone marrow failure is the shared endpoint of essentially all Fanconi complementation groups and therefore says more about the FA pathway than about UBE2T specifically. The independent evidence that makes the HSC assignment gene-specific is the somatic reversion of a UBE2T allele in a patient's own haematopoietic stem cells, which rescued the marrow. Virts EL et al. 2015
  9. E9strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

    The haematopoietic stem cell is the cell type in which UBE2T function is limiting in humans: in the first patient identified with biallelic germline UBE2T mutations - an AluY-mediated paternal deletion and maternal duplication of exons 2-6 - the maternal duplicated allele spontaneously reverted to a wild-type allele by monoallelic recombination at the duplicated AluY repeat IN THE PATIENT'S HAEMATOPOIETIC STEM CELLS, thereby preventing bone marrow failure; the mutations otherwise produced a cellular phenotype resembling biallelic defects in early FA genes with absent FANCD2 monoubiquitination.

    AluY-mediated germline deletion, duplication and somatic stem cell reversion in UBE2T defines a new subtype of Fanconi anemia. · Virts EL, Jankowska A, Mackay C, Glaas MF, Wiek C, Kelich SL, Lottmann N, Kennedy FM, Marchal C, Lehnert E, Scharf RE, Dufour C, Lanciotti M, Farruggia P, Santoro A, Savasan S, Scheckenbach K, Schipper J, Wagenmann M, Lewis T, Leffak M, Farlow JL, Foroud TM, Honisch E, Niederacher D, Chakraborty SC, Vance GH, Pruss D, Timms KM, Lanchbury JS, Alpi AF, Hanenberg H · Hum Mol Genet 2015
    PMID 26085575DOI
    What this evidence cannot show

    A single patient, so the reversion observation is n=1 - though it is an internally controlled natural experiment. Human germline and somatic genetics, not leukaemia and not KMT2A-rearranged. The same paper's breast-cancer-susceptibility observations are a separate and weaker claim not relied on here. Read: abstract only.

    Evidence that argues against this (1)
    • Somatic reversion rescuing the marrow shows the HSC is where the deficiency BITES, not that UBE2T is required in HSCs more than elsewhere - it may simply be the tissue with the highest replicative demand and the least tolerance for unrepaired interstrand crosslinks. The distinction matters for a therapeutic argument: a tissue that fails first under a pathway defect is not necessarily a tissue with a special requirement for the gene. Hira A et al. 2015
  10. E_q66_loc1strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

    UBE2T reaches the chromatin fraction on its own: UBE2T and FANCD2 access the chromatin subcellular fraction INDEPENDENTLY of the Fanconi anaemia core complex, and the E3 ligase activity that produces FANCD2 monoubiquitination is determined not by assembly of the core complex but by its DNA-damage-induced localisation to chromatin, so monoubiquitination is regulated by formation of an active E2/E3 holoenzyme ON CHROMATIN rather than by multiprotein complex assembly.

    PMID 17938197DOI
    What this evidence cannot show

    Chromatin fractionation and biochemistry in non-haematopoietic cultured human and chicken DT40 systems of the FA field, not in leukaemia and not in a KMT2A-rearranged cell. This is a fraction-based localisation - the chromatin-bound versus soluble axis - and not an image, so it carries no information about which nuclear compartment or body UBE2T occupies. The result is about damage-induced recruitment, so the resting-state distribution is not bounded by it. Read: abstract only. Identifiers copied field by field from the efetch record fetched 2026-09-21, ArticleId path anchored per brief rule 81.

    Evidence that argues against this (1)
    • UBE2T inactivates itself where it works, so a chromatin-bound pool is not a steady-state address: UBE2T undergoes automonoubiquitination in vivo, this modification is stimulated by FANCL and it INACTIVATES UBE2T. A fractionation snapshot therefore mixes active and self-inactivated protein, and the fraction assay cannot tell them apart. Machida YJ; Machida Y; Chen Y; Gurtan AM; Kupfer GM; D'Andrea AD; Dutta A 2006
  11. E_q66_loc2moderate confidence 3 of 5: One strong study, or several smaller consistent ones.dataset

    The reviewed human UniProt record for UBE2T (Q9NPD8, 197 aa, primary gene name UBE2T) annotates exactly one subcellular location, Nucleus, at ECO:0000269 - no cytoplasmic, membrane or organellar pool is recorded, and no subnuclear body is named.

    UniProtKB Q9NPD8 (UBE2T_HUMAN), Ubiquitin-conjugating enzyme E2 T, 197 aa - SUBCELLULAR LOCATION comment · UniProt Knowledgebase, reviewed human record, fetched 2026-09-21 2026
    What this evidence cannot show

    A single-line database annotation. Absence of a second compartment in UniProt is absence of a curated source, not evidence that no second pool exists, and this is the distinction brief rule 69b insists on: record a field absent rather than searching harder and presenting the result as though it came from the field. Accession and length read back from the fetched record and match this entry's stored uniprot and length_aa (Q9NPD8 / 197).

    Evidence that argues against this (1)
    • A bare Nucleus annotation is the least informative possible answer for a 197-residue enzyme whose job is damage-dependent, and it conflicts in emphasis with the fractionation result: PMID 17938197 shows the interesting quantity is the DAMAGE-INDUCED chromatin pool, which a static compartment label cannot express. The database row and the experiment are not in conflict, but only the experiment is usable. Alpi A; Langevin F; Mosedale G; Machida YJ; Dutta A; Patel KJ 2007
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