ELP3 - the catalytic subunit, the only Elongator protein with a real acetyltransferase domain, and the one whose loss in mouse blood causes marrow failure and then p53-mutant leukaemia

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.

• THE SIGN IS PROBABLY WRONG, AND THIS IS THE STRONGEST BITE-BACK IN THE BEAT. In mouse haematopoiesis, loss of the catalytic Elongator subunit causes bone marrow failure and then p53-mutated leukaemia/lymphoma, and p53 and Elongator inactivation cooperatively promote tumorigenesis. Germline ELP1 loss predisposes to paediatric medulloblastoma. Both directional results in the field make Elongator tumour-suppressive, so an ELP3 inhibitor in a leukaemia is predicted by the available data to be leukaemogenic.
• Essential-function toxicity is measured, not speculative: ELP3 is required in nearly every DepMap line (-0.965 across 1,208), and its loss in mouse marrow kills committing progenitors and compromises stem-cell grafting. Any ELP3-directed agent would be predicted to cause marrow failure at an effective dose.
• The toxicity would be distributed rather than targeted. ELP3's established output is a tRNA wobble modification required for accurate decoding, so loss produces codon-dependent translational reprogramming and an unfolded-protein response across the whole proteome - the worst possible shape for a therapeutic window, and the exact mechanism by which ELP1-mutant medulloblastomas become proteostatically fragile.
• In ALS, MORE ELP3 is protective - it extends survival in SOD1-G93A mice and its expression is reduced in patient motor cortex. An inhibitor of this enzyme would be expected to worsen a motor-neuron phenotype, and ELP3 is annotated as an ALS disease modifier.
• Do not read the ALK result as a therapeutic handle. ELP3's Y202 phosphorylation is required for an ALK-positive tumour's growth, which reads like a target - but the experiment is an overexpressed phospho-mutant in cells that still carry endogenous ELP3, the tumour is ALK-positive lymphoma and not a KMT2A-rearranged leukaemia, and the intervention that already works in that disease is an ALK inhibitor.
• No ELP3-directed chemical matter exists, and this is recorded as UNMEASURED rather than zero: the ChEMBL activity endpoint returned HTTP 500 on three attempts on 2026-09-22 and no row count was obtained. An instrument failure is not a result - which is the same lesson the empty-querytranslation defect in this entry teaches.

1. Which substrate does the human ELP3 GNAT pocket actually use in a haematopoietic cell? The histone assignment rests on two contradictory 2002 human preparations never repeated; the tRNA assignment is structurally beautiful and carries an EC number inferred by similarity; and the two demonstrated in vivo protein substrates are a fly synaptic protein and alpha-tubulin, on which UniProt's own record contradicts itself. A calibrated ICeChIP or a clean human reconstitution would settle a twenty-four-year-old question that this graph would otherwise inherit as settled.
2. Is any Elongator subunit phosphorylated in a KMT2A-rearranged cell? ELP3 is an ALK substrate at Tyr202 and its phospho-site is required for an ALK fusion's growth and gene expression; this graph's central fusion carries P-TEFb/CDK9 in its complex. This is a re-analysis of existing phosphoproteomics, not an experiment.
3. Is there a nucleolar Elongator pool? ELP3 carries GO:0005730 and nothing else in this beat does, no imaging or fractionation supports it, and this project holds a standing hypothesis that tRNA and ribosome biology is the unmeasured dependency in KMT2A-rearranged leukaemia. One immunofluorescence panel would convert a GO term into a measurement or delete it.
4. Does the mouse Elp3 marrow phenotype reproduce in a KMT2A-fusion background? The result predicts that Elongator loss is PERMISSIVE for leukaemia rather than protective, which is the opposite of what an elongation-cofactor hypothesis predicts, and it is the single experiment that would tell this project whether to pursue Elongator at all. Cost: crossing an existing conditional allele into an existing model.
5. Do the two p53 links connect? Loss of Elp3 activates a p53-dependent checkpoint in haematopoiesis (2021) and overexpression of ELP5/DERP6 activates p53 transcriptional activity in a reporter assay (2006), and no paper cites both. Recorded as a convergence worth one experiment and explicitly not as a pattern.
6. Is ELP3 at mitochondria? One 2009 paper with two antibodies says yes; UniProt has not adopted it; nothing has repeated it.

1. E1established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database

   ELP3 (Q9H9T3, ELP3_HUMAN) is a 547-residue protein carrying a radical SAM core domain at 82-372 and an N-acetyltransferase domain at 396-547, whose UniProt recommended alternative name is tRNA uridine(34) acetyltransferase (EC 2.3.1.311) and whose FUNCTION comment states that a protein lysine acetyltransferase activity is unclear in vivo with recent evidence suggesting ELP3 primarily acts as a tRNA acetyltransferase and that it is not a major acetyltransferase of tubulin; it carries Tyr202 as a phosphotyrosine by ALK, an amyotrophic-lateral-sclerosis DISEASE comment marked as a disease modifier, a TISSUE SPECIFICITY comment for cerebellum and spinal motor neurons, and the GO term GO:0005730 nucleolus.

   UniProtKB Q9H9T3 (ELP3_HUMAN) - reviewed human record, length 547 aa · UniProt Consortium · UniProtKB 2026
   ▸What this evidence cannot show

   Accession resolved 2026-09-22 by gene_exact:ELP3 AND organism_id:9606 AND reviewed:true with gene_primary and length read back (rules 62, 65, 66): exactly one reviewed human row, primary gene name ELP3, entry ELP3_HUMAN, 547 aa, NO gene synonyms at all. Evidence codes recorded rather than flattened, because on this record they are the story: the tRNA-modification clause is ECO:0000269:29415125 (experimental); the catalytic activity and the EC number are ECO:0000250 BY SIMILARITY from a non-human ortholog (D5VRB9), so UniProt RENAMED the human protein on an inferred activity; the 'unclear in vivo' judgement is the curator's own reading of PubMed:29415125; and the two domain boundaries are ECO:0000255 from PROSITE rules PRU01266 and PRU00532, i.e. sequence-model predictions rather than structures. THE RECORD ALSO CONTRADICTS ITSELF IN ADJACENT SENTENCES: FUNCTION says 'Not a major acetyltransferase of tubulin (PubMed:22153374)' and, two clauses later, 'regulates the migration and branching of projection neurons in the developing cerebral cortex, through a process depending on alpha-tubulin acetylation (PubMed:19185337)'. Both are ECO:0000269. Reported, not resolved.

   ▸Evidence that argues against this (1)

   • The clause 'Not a major acetyltransferase of tubulin' is coded to PMID 22153374, whose ABSTRACT contains no such statement - it reports that ELP3 acetylates the ELKS-family protein Bruchpilot in Drosophila neurons. The negative may well be in that paper's body, but a beat quoting the UniProt clause from the abstract cannot verify it, and the same record cites PMID 19185337 in the opposite direction. Read both bodies before repeating either clause. Creppe C et al. 2009
2. E2established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.review

   In the current structural literature ELP3 is described as the catalytic subunit of Elongator containing a radical S-adenosyl-L-methionine domain and a PUTATIVE histone acetyltransferase domain, while the ELP4/5/6 subcomplex possesses ATP-modulated tRNA-binding activity, and how Elongator performs its multiple functions remains poorly understood.

   Structural insights into the function of Elongator. · Dalwadi U, Yip CK · Cell Mol Life Sci 2018
   PMID 29332244DOI
   ▸What this evidence cannot show

   A REVIEW, cited for nomenclature and for the field's own hedging word 'putative' - verified in its abstract - and not as primary evidence for or against any activity.

   ▸Evidence that argues against this (1)

   • 'Putative' is the 2018 midpoint of a movement that has gone further: UniProt's 2026 record says the protein-lysine activity is unclear in vivo and renames the enzyme after its tRNA substrate. Citing only the review understates how far the assignment has receded. UniProt Consortium 2026
3. E3established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paper

   Four cryo-EM structures of the human ELP123 subcomplex containing ELP3, bound to tRNA and cofactors, resolve four stages of the wobble-uridine modification reaction at resolutions to 2.9 Angstrom, showing that tRNA binding exposes the conserved uridine at position 33 which triggers acetyl-CoA hydrolysis, identifying conserved residues required for radical-based acetylation of U34, and profiling the molecular effects of patient-derived mutations - with no histone, nucleosome or chromatin template anywhere in the reaction series.

   Cryo-EM structures of the human Elongator complex at work. · Abbassi NE, Jaciuk M, et al. · Nat Commun 2024
   PMID 38750017DOI
   ▸What this evidence cannot show

   Human protein and human structural work, to 2.9 Angstrom; abstract read, full text not read. PDB identifiers 8PTX/8PTY/8PTZ/8PU0 taken from the UniProt cross-reference list of Q9H9T3, not read off the paper; no residue span in this entry was read off a deposit (this project's PDB rule). The absence of a histone in the series is not evidence against a histone activity - nobody put one in - so this bounds the human structural literature and not the enzyme.

   ▸Evidence that argues against this (1)

   • No Elongator structure in any species has been solved with a histone tail or a nucleosome, so the structural literature cannot adjudicate the histone question in either direction. The GNAT pocket demonstrably accepts a protein substrate in vivo (Bruchpilot in Drosophila neurons), so 'the structures show tRNA' is not 'the pocket takes only tRNA'. Miśkiewicz K et al. 2011
4. E4strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

   IN MOUSE MODELS OF CONDITIONAL Elp3 INACTIVATION, loss of Elp3 - the catalytic subunit of Elongator - causes bone marrow failure by inducing death in committing progenitors and compromises the grafting activity of haematopoietic stem cells, through a p53-dependent checkpoint resembling a misguided amino-acid deprivation response accompanied by Atf4 overactivation and increased protein synthesis; deletion of p53 rescues haematopoiesis, but loss of Elp3 prompts the development of p53-mutated leukaemia/lymphoma, and inactivation of p53 and Elongator cooperatively promotes tumorigenesis.

   Loss of tRNA-modifying enzyme Elp3 activates a p53-dependent antitumor checkpoint in hematopoiesis. · Rosu A, El Hachem N, et al. · J Exp Med 2021
   PMID 33507234DOI
   ▸What this evidence cannot show

   MOUSE conditional knockout of Elp3, not human ELP3, and not a KMT2A-rearranged system - stated in the claim rather than only here, per this project's rule 73. Abstract read; full text not read; the lineage of the resulting leukaemia/lymphoma is not specified in the abstract, so this entry does not assign it to a lineage. This is the ONLY haematopoietic experiment in the entire Elongator literature: Elongator[tiab] AND leukemia[tiab] returns exactly 1 record and this is it. A complete genetic knockout bounds what total loss does and says nothing about partial pharmacological inhibition - although in this instance the partial-loss human phenotype (familial dysautonomia, an ELP1 splicing hypomorph) has no reported haematopoietic component at all, and FD patients' lymphoblasts carry mostly wild-type message.

   ▸Evidence that argues against this (2)

   • The tumour phenotype is p53-CONDITIONAL, which limits how far the tumour-suppressor reading generalises: Elp3 loss alone caused marrow failure, and leukaemia/lymphoma appeared in the p53-compromised background. A reader wanting 'Elongator loss is oncogenic' must carry the p53 context. What survives unconditionally is that Elongator is REQUIRED for normal haematopoietic differentiation and stem-cell grafting, which is by itself a reason not to inhibit it in a marrow disease. Waszak SM et al. 2020
   • Nothing in this paper measures Elongator in a KMT2A-rearranged cell, and the result is not evidence about the fusion. It is evidence about the SIGN a fusion-directed experiment should expect, which is the opposite of the one that motivated this beat. IntAct/EMBL-EBI 2026
5. E5moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper

   ELP3 is modified by tyrosine phosphorylation, anaplastic lymphoma kinase (ALK) is the major tyrosine kinase responsible, ELP3 is phosphorylated in tumour cells expressing the oncogenic NPM-ALK fusion protein, Tyr202 is the major ALK phosphorylation site, and introducing a Y202 phosphorylation mutant of ELP3 into ALK-positive tumour cells reduces cell growth and impairs gene expression.

   ELP3 Acetyltransferase is phosphorylated and regulated by the oncogenic anaplastic lymphoma kinase (ALK). · Li MT, Liang JY, et al. · Biochem J 2019
   PMID 31341009DOI
   ▸What this evidence cannot show

   ALK-positive tumour cell lines expressing NPM-ALK; abstract read, full text not read. This is the ONLY connection between any Elongator subunit and any fusion oncoprotein that this beat could find, and the direction is that the fusion MODIFIES Elongator rather than recruiting it. The Y202 mutant experiment is an overexpression rescue in a background that still contains endogenous ELP3, so it is a dominant-negative-style readout rather than a clean genetic test. UniProt carries the site as Modified residue 202, 'Phosphotyrosine; by ALK', ECO:0000269:31341009 plus ECO:0007744:15592455 (a mass-spectrometry dataset), and a second phosphotyrosine at 251 from the same paper.

   ▸Evidence that argues against this (1)

   • It does not transfer to KMT2A::AFF1. NPM1::ALK is a constitutively active tyrosine kinase; KMT2A::AFF1 is a chromatin-targeting scaffold with no kinase activity of its own. The analogy is in FORM - a fusion oncoprotein acting on a cofactor that is not its partner - and not in mechanism. The question it licenses is narrow and cheap: this graph's central fusion recruits P-TEFb/CDK9, so it has a kinase in its complex, and nobody has asked whether any Elongator subunit is phosphorylated in a KMT2A-rearranged cell. Dalwadi U et al. 2018
6. E6strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.database

   No paper names ELP3 and a KMT2A fusion together: measured 2026-09-22 with one [tiab] tag per term and querytranslation asserted non-empty, ELP3[tiab] = 202, ELP3[tiab] AND KMT2A[tiab] = 0, AND MLL[tiab] = 0, AND leukaemia[tiab] = 0, AND leukemia[tiab] = 1 (the mouse Elp3 haematopoiesis paper), and the mandatory complex form Elongator[tiab] AND KMT2A[tiab] = 0 and AND MLL[tiab] = 0, against positive controls through the identical shape of AFF1[tiab] AND KMT2A[tiab] = 104, DOT1L[tiab] AND KMT2A[tiab] = 30 and KMT2A[tiab] AND histone[tiab] = 218.

   NCBI E-utilities esearch over PubMed and GEO DataSets, run 2026-09-22 by Q98 through a wrapper that refuses any response with an empty querytranslation · Oncofusion knowledge-graph project (Q98-elongator-smyd3) · NCBI E-utilities 2026
   ▸What this evidence cannot show

   THIS IS THE ABSENCE THE INSTRUMENT ALARM ALMOST FABRICATED. INSTRUMENT ALARM RECORDED WITH THE RESULT. On the first pass of this beat's symbol sweep, ELP3[tiab] and ELP6[tiab] each returned a well-formed esearchresult with count 0, querytranslation EMPTY STRING, and errorlist and warninglist both {}. Re-run minutes later through the identical code path they return 202 and 43. Every count in this entry was therefore taken through a guarded wrapper that REFUSES any response whose querytranslation is empty and retries. A zero with an empty querytranslation is an instrument failure, not a result, and nothing else in the response says so. Zero in TITLES AND ABSTRACTS ONLY; supporting figures and supplementary tables not searched (rule 80). Name list searched: ELP3, KAT9 (6 records), and the complex form 'Elongator' (608 records) - the complex form is mandatory for a subunit absence (rule 64) and returns 0 against both KMT2A and MLL. Archive half: GEO DataSets 'ELP3 AND leukemia' = 0 against a control of 'KMT2A' = 2,300, and that zero is ITSELF soft - a mouse Elp3 leukaemia/lymphoma paper exists (E4), so the GEO metadata index is missing a literature that exists, which is a reason to treat the archive arm as corroboration rather than as an independent bound. PRIDE is not empty: keyword ELP3 returns 14 projects and Elongator returns 24, against a KMT2A control of 37, so the proteomics archive is the place a positive would be found and it was not read project by project.

   ▸Evidence that argues against this (1)

   • The repository-side check is the one that would overturn this and does not: grepping this project's five KMT2A-fusion interactome analyses for ELP1 through ELP6, Elongator and SMYD3 returns nothing. This project has previously declared a literature empty while citing the disproving paper in four of its own entries, so this grep is the load-bearing half of the absence. What is NOT bounded: 14 PRIDE projects mention ELP3 and none was opened, and ELP3 appears as an A-minus-class prey in this repository's own copy of the Hein 2015 human interactome (analyses/hein-abundance-versus-confidence) - which is a proteome-scale atlas and not a KMT2A bait, so it is a lead and not a contact. IntAct/EMBL-EBI 2026
7. E7moderate confidence 3 of 5: One strong study, or several smaller consistent ones.database

   IntAct REST returns 107 interaction records for ELP3 (Q9H9T3) spanning 66 distinct molecules, which include POLR2A - the largest subunit of RNA polymerase II - and all five other Elongator subunits, and which include none of KMT2A, MEN1, AFF1, AFF4, MLLT1, MLLT3, MLLT10, DOT1L, PSIP1, CDK9, ELL, KAT7, WDR5 or HOXA9.

   IntAct molecular interaction database, REST endpoint findInteractions (not PSICQUIC) · IntAct/EMBL-EBI · IntAct 2026
   ▸What this evidence cannot show

   Queried 2026-09-22 through IntAct REST findInteractions and NOT PSICQUIC (rule 93), with the documented control findInteractions/Q03164 returning 376 records, reproducing rule 93's figure exactly. An IntAct absence is 'measured-not-curated' for any partner appearing only in an uncurated proteome, and this project has established that the index fusion's own AP-MS interactome (PMID 29777171) has never been entered into IntAct. Partner names read from moleculeA/moleculeB gene-symbol fields across paged results.

   ▸Evidence that argues against this (1)

   • A POLR2A record is not evidence of a KMT2A-fusion contact and must not be read as one - Pol II is the most promiscuously curated partner in the database, and a KMT2A fusion and an Elongator subunit sharing it is a statement about Pol II. The recovery of all five sibling subunits is, however, a useful internal control that the query reached the right protein. Hawkes NA et al. 2002
8. E8moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper

   Human Elongator purified from HeLa cells has histone acetyltransferase activity specific to histone H3 and much weaker on H4, interacts directly with RNA polymerase II, and facilitates Pol II transcription in a chromatin- and acetyl-CoA-dependent manner while failing to interact with other factors that let Pol II traverse nucleosomes.

   Human Elongator facilitates RNA polymerase II transcription through chromatin. · Kim JH, Lane WS, et al. · Proc Natl Acad Sci U S A 2002
   PMID 11818576DOI
   ▸What this evidence cannot show

   The paper's own first sentence is decisive for how far it can be pushed: the purified complex 'was found to be composed of THREE polypeptides'. A three-subunit preparation cannot establish which subunit carries the activity, and the contemporaneous six-subunit purification found a three-subunit core to have NO HAT activity. Abstract read; full text not read. Cited for the Pol II contact and the chromatin/acetyl-CoA dependence, which are its robust content.

   ▸Evidence that argues against this (1)

   • Directly contradicted on composition-versus-activity by PMID 11714725, in which the three-subunit core form has no HAT activity despite containing catalytic ELP3. Two human purifications from 2002 disagree, and neither histone assay has been repeated in human cells in the twenty-four years since - so the human Elongator HAT claim rests on an unreplicated result with a same-year contradiction. Hawkes NA et al. 2002
9. E9strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

   ELP3 modifies amyotrophic lateral sclerosis through tRNA modification: ELP3 attenuates the axonopathy of mutant-SOD1 and mutant-C9orf72 ALS zebrafish models, ELP3 expression extends survival and attenuates denervation in the SOD1-G93A mouse, ELP3 depletion in vitro reduces the modified wobble uridine mcm5s2U and increases the abundance of insoluble mutant SOD1 in a manner reverted by exogenous ELP3, and ELP3 expression is reduced in the motor cortex of ALS patients and correlates with mcm5s2U levels.

   Elongator subunit 3 (ELP3) modifies ALS through tRNA modification. · Bento-Abreu A, Jager G, et al. · Hum Mol Genet 2018
   PMID 29415125DOI
   ▸What this evidence cannot show

   Zebrafish and mouse models plus human post-mortem motor cortex; abstract read, full text not read. This is the paper UniProt cites for ELP3's tRNA function and for its judgement that the protein-lysine activity is unclear in vivo, so it is the load-bearing citation for the current curated position - and it is worth noting that it is a NEURODEGENERATION paper, not an enzymology paper. The direction here is that MORE ELP3 is protective, which is a third independent result in which loss of Elongator function is the harmful state.

   ▸Evidence that argues against this (1)

   • This paper does not test a histone activity and therefore cannot exclude one; it shows that the tRNA output is the one that matters for ALS. UniProt's inference from it to 'ELP3 primarily acts as a tRNA acetyltransferase' is the curator's reading, coded ECO:0000269 to this paper, and generalises a disease-modifier result to a statement about the enzyme's principal activity. UniProt Consortium 2026
10. E10strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

    IN DROSOPHILA NEURONS, ELP3 is necessary and sufficient to acetylate the ELKS-family protein Bruchpilot, an integral component of the presynaptic density, and in elp3 mutants presynaptic densities assemble normally but their cytoplasmic extensions cover a larger area, producing increased vesicle tethering and more proficient neurotransmitter release.

    ELP3 controls active zone morphology by acetylating the ELKS family member Bruchpilot. · Miśkiewicz K, Jose LE, et al. · Neuron 2011
    PMID 22153374DOI
    ▸What this evidence cannot show

    Drosophila, neurons, a non-histone protein substrate - stated in the claim. Abstract read; full text not read. Cited for the decisive general point that ELP3's GNAT pocket does accept a PROTEIN substrate in vivo, so 'primarily a tRNA enzyme' is a statement about the dominant activity and not a demonstration that protein acetylation is impossible. UniProt additionally cites this paper for 'Not a major acetyltransferase of tubulin', a clause its abstract does not contain - flagged at E1 and not repeated as fact here.

    ▸Evidence that argues against this (1)

    • A cytoplasmic, synaptic, invertebrate protein substrate is very weak support for a nuclear histone substrate in a human haematopoietic cell. If anything it points the other way, by showing that when ELP3's protein-acetyltransferase activity has been demonstrated in vivo the substrate was not a histone. Abbassi NE et al. 2024
11. E11strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

    Silencing either the Elongator scaffold Elp1 or the catalytic subunit Elp3 cell-autonomously delays migration and impairs branching of cortical projection neurons; neurons defective in Elongator show reduced levels of acetylated alpha-tubulin; expressing a non-acetylatable alpha-tubulin mutant produces comparable defects; and Elp3 promotes alpha-tubulin acetylation and counteracts HDAC6-mediated deacetylation of that substrate in vitro.

    Elongator controls the migration and differentiation of cortical neurons through acetylation of alpha-tubulin. · Creppe C, Malinouskaya L, et al. · Cell 2009
    PMID 19185337DOI
    ▸What this evidence cannot show

    Mouse cortical neurons in vivo plus in vitro enzymology; abstract read, full text not read. Note the paper's own framing - it calls Elongator 'the multisubunit HISTONE ACETYLTRANSFERASE Elongator complex' while demonstrating that the relevant substrate is alpha-tubulin, which is a compact illustration of how the complex's name outran its measured substrates. Cited as a second demonstrated non-histone protein substrate and as ELP3's cortical-neuron cell-type assignment.

    ▸Evidence that argues against this (1)

    • UniProt's own ELP3 record carries, two clauses after citing this paper for the alpha-tubulin-dependent process, the statement 'Not a major acetyltransferase of tubulin (PubMed:22153374)'. Both clauses are ECO:0000269. The record contradicts itself on tubulin and this entry reports that rather than choosing a side. Miśkiewicz K et al. 2011
12. E13weak confidence 2 of 5: Preliminary, small, indirect, or not yet peer reviewed.paper

    The human gene DERP6 - now ELP5, the accessory-lobe subunit that bridges ELP3 to ELP4 - was cloned from a testis library, is ubiquitously expressed with high levels in heart, brain, liver, skeletal muscle and testis, localised to cytoplasm WHEN OVEREXPRESSED in cultured cells, and its overexpression activated the transcriptional activity of p53 in reporter assays.

    Cloning and characterization of the human gene DERP6, which activates transcriptional activities of p53. · Yuan J, Tang W, et al. · Mol Biol Rep 2006
    PMID 16850183DOI
    ▸What this evidence cannot show

    A 2006 gene-cloning paper: Northern blot, overexpression localisation and a luciferase reporter, with no loss-of-function arm. Abstract read; full text not read. Cited in THIS entry only for the convergence - two independent p53 links on two different Elongator subunits, fourteen years apart, with no paper citing both - and the full treatment lives in gene-elp5. Its p53 direction is also the OPPOSITE of the haematopoietic result's: here more ELP5 activates p53, there loss of Elp3 activates a p53 checkpoint.

    ▸Evidence that argues against this (1)

    • A reporter assay driven by overexpression of a complex subunit is very weak evidence about the endogenous complex, and the two p53 observations may share nothing but the word p53. Recorded as a convergence worth one experiment, explicitly NOT as a pattern - the same standing this graph gave the SMYD3 convergence in cycle 53. Rosu A et al. 2021
13. E15moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper

    Two of ELP3's four UniProt SUBCELLULAR LOCATION evidence codes rest on a single HeLa SILAC study of proteome-wide protein turnover and subcellular distribution, which contains no ELP3-specific experiment - ELP3 is one row of a proteome in it.

    Systematic analysis of protein pools, isoforms, and modifications affecting turnover and subcellular localization. · Ahmad Y, Boisvert FM, et al. · Mol Cell Proteomics 2012
    PMID 22002106DOI
    ▸What this evidence cannot show

    Rule 91, defect direction, and a variant of the shape rule 92 warns about: in a proteome-scale fractionation every protein is measured, so an ECO:0000269 derived from it is a real measurement and a very weak pointer - it tells you a curator saw a number, not that anyone studied this protein's localisation. Abstract read; full text not read; ELP3's row was not extracted from the paper's supplementary data, so this entry does not quote a compartment ratio. Reported, not edited: this is UniProt's record and not a file this beat owns.

    ▸Evidence that argues against this (1)

    • The annotation is not wrong for being weakly sourced - ELP3's nuclear pool is independently supported by the Elongator purifications, and the proteome study is a legitimate measurement. The defect is in the POINTER, which is exactly rule 91's claim: an evidence code tells you a curator read an experiment, not that the paper is about your fact. Hawkes NA et al. 2002
14. E16weak confidence 2 of 5: Preliminary, small, indirect, or not yet peer reviewed.paper

    Immunofluorescence with two different antibodies against ELP3 localises ELP3 to mitochondria in HeLa cells and to actin-like filaments and actin-rich sites at the edges of spreading cells, suggesting roles in mitochondrial function and in actin organisation and cell motility.

    ELP3 localises to mitochondria and actin-rich domains at edges of HeLa cells. · Barton D, Braet F, et al. · Neurosci Lett 2009
    PMID 19429107DOI
    ▸What this evidence cannot show

    The ONLY antibody-based localisation of human ELP3 this beat found, and it is a short 2009 Neuroscience Letters report. Two independent antibodies is the right control and the study has no fractionation, no co-localisation quantification reported in the abstract, and no rescue. HeLa only. Abstract read; full text not read. Recorded because it puts the catalytic subunit at neither chromatin nor the bulk cytosolic tRNA pool, and because UniProt does not carry a mitochondrial compartment for ELP3 at all.

    ▸Evidence that argues against this (1)

    • Mitochondrial immunofluorescence with anti-ELP3 antibodies in a single cell line is the class of result that most often fails to replicate, and UniProt has not adopted it despite carrying weaker-sourced calls for the same protein - which is itself a signal. Read as a lead, not a compartment. UniProt Consortium 2026
15. E17strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

    Allelic variants of ELP3 are associated with amyotrophic lateral sclerosis in three human populations comprising 1,483 people (P = 1.96e-9), two independent loss-of-function ELP3 mutations were recovered in a Drosophila mutagenesis screen for genes important in neuronal communication and survival, knockdown of ELP3 in zebrafish embryos causes dose-dependent motor axonal abnormalities, and risk-associated ELP3 genotypes correlate with reduced brain ELP3 expression.

    Variants of the elongator protein 3 (ELP3) gene are associated with motor neuron degeneration. · Simpson CL, Lemmens R, et al. · Hum Mol Genet 2009
    PMID 18996918DOI
    ▸What this evidence cannot show

    A 2009 candidate-and-microsatellite association study (1,884 markers) plus fly and fish functional arms; abstract read, full text not read. A P value of 1.96e-9 from 1,884 markers in 1,483 people predates genome-wide association standards and UniProt records the result cautiously - the DISEASE comment's note is 'The gene represented in this entry may act as a disease MODIFIER', not a cause. Cited for the disease-modifier status and for ELP3's cerebellum and spinal-motor-neuron tissue assignment, which UniProt codes ECO:0000269 to this paper.

    ▸Evidence that argues against this (1)

    • The association has been superseded in mechanism rather than magnitude: the 2018 follow-up establishes the ALS link through tRNA modification and mcm5s2U levels, with more ELP3 protective, which is a cleaner statement than an allelic association. Neither is evidence about any cancer. Bento-Abreu A et al. 2018
16. E12_HAT_YEASTestablished confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paper

    In YEAST, intact Elongator is a histone H3 and H4 acetyltransferase whose predominant sites are H3K14 and H4K8, it acetylates core and nucleosomal substrates where isolated Elp3 is not specific, the three smallest subunits Elp4, Elp5 and Elp6 are REQUIRED for that HAT activity, and multiply-acetylated H3 and H4 are reduced in vivo in ELP3-null cells.

    Elongator is a histone H3 and H4 acetyltransferase important for normal histone acetylation levels in vivo. · Winkler GS, Kristjuhan A, et al. · Proc Natl Acad Sci U S A 2002
    PMID 11904415DOI
    ▸What this evidence cannot show

    Saccharomyces cerevisiae throughout - not human, not haematopoietic, not a fusion system (this project's rule that the system belongs in the claim, not only the caveat). Abstract read; full text not read. The in vivo arm is a chromatin immunoprecipitation of bulk acetylated H3/H4 in an ELP3 deletion, so it establishes that Elongator contributes to steady-state acetylation levels and not that Elongator is the writer at any named gene. The requirement for the small subunits is a requirement for HAT ACTIVITY OF THE COMPLEX and does not make ELP4, ELP5 or ELP6 catalytic.

    ▸Evidence that argues against this (1)

    • The same paper's own framing has been overtaken. UniProt's current human ELP3 record renames the protein 'tRNA uridine(34) acetyltransferase' and states that protein-lysine acetyltransferase activity is unclear in vivo; the 2018 structural review calls the ELP3 HAT domain putative. A 2002 yeast result is not withdrawn by a 2026 database opinion, but a beat that cites only this paper is quoting the high-water mark of a claim that has receded. Dalwadi U et al. 2018
17. E12_HAT_HUMANstrong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

    In HUMAN HeLa cells the purified Elongator complex exists in two forms and only the six-subunit holo-Elongator has histone acetyltransferase activity against H3 and H4: the three-subunit core form has NO HAT activity despite containing the catalytic ELP3 subunit, and Elongator is a component of early elongation complexes formed in HeLa nuclear extracts and interacts directly with RNA polymerase II in solution.

    Purification and characterization of the human elongator complex. · Hawkes NA, Otero G, et al. · J Biol Chem 2002
    PMID 11714725DOI
    ▸What this evidence cannot show

    Biochemical purification from HeLa; abstract read, full text not read. This is the paper that reassigned two proteins to Elongator - it identifies StIP1 (ELP2) and IKAP (ELP1) as subunits of the human complex - so it is simultaneously the source of the small-subunit requirement in human cells and the source of two of the identity traps recorded in this beat. It is ALSO the resolution of a disagreement this graph already records: gene-elp4 notes that a contemporaneous human purification recovered only three polypeptides WITH HAT activity (PMID 11818576) and leaves the disagreement open; this paper's three-subunit core has NO HAT activity. Both are 2002, both are human, and they disagree. Recorded as a live disagreement, not as a resolution in either direction.

    ▸Evidence that argues against this (1)

    • THE DIRECT CONTRADICTION, and it is not resolved. A human Elongator purified from HeLa the same year was composed of THREE polypeptides and DID have HAT activity specific to histone H3, facilitating Pol II transcription in a chromatin- and acetyl-CoA-dependent manner. Complex composition determined by purification depends on the tag, the salt and the cell type, so 'three subunits, no HAT' and 'three polypeptides, HAT' are both properties of preparations. No later human paper this beat could find repeats either HAT assay. Kim JH et al. 2002
18. E12_TRNA_NOWstrong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

    The current curated and structural position is that Elongator is a tRNA wobble-uridine modification enzyme: UniProt names human ELP3 'tRNA uridine(34) acetyltransferase' (EC 2.3.1.311) and states that its protein-lysine acetyltransferase activity is unclear in vivo, and every high-resolution structure of human Elongator is of the ELP123 subcomplex bound to tRNA and cofactors, resolving four stages of the U34 acetylation reaction with no histone in the series.

    Cryo-EM structures of the human Elongator complex at work. · Abbassi NE, Jaciuk M, et al. · Nat Commun 2024
    PMID 38750017DOI
    ▸What this evidence cannot show

    Cryo-EM to 2.9 Angstrom of human ELP123 with tRNA; abstract read, full text not read. An absence of histone in a structural series is not evidence that histones are not substrates - nobody put one in - so this bounds what the human structural work SHOWS and not what Elongator can do. The UniProt FUNCTION clause quoted here is coded ECO:0000269 to PMID 29415125 for the tRNA half, while the replacement catalytic activity and the EC number are ECO:0000250 BY SIMILARITY from a non-human ortholog: UniProt renamed the human protein on an inferred activity, which is worth knowing before quoting the new name as settled.

    ▸Evidence that argues against this (1)

    • ELP3 does demonstrably acetylate at least one non-histone PROTEIN in vivo: in Drosophila neurons ELP3 is necessary and sufficient to acetylate the ELKS-family protein Bruchpilot at presynaptic densities, with a structural and a neurotransmitter-release phenotype. So 'primarily a tRNA enzyme' is a statement about the dominant activity, not a demonstration that the GNAT pocket cannot take a protein substrate. Note also that UniProt cites this same paper for 'Not a major acetyltransferase of tubulin', a clause its abstract does not contain - read the body before quoting that negative. Miśkiewicz K et al. 2011
19. E14weak confidence 2 of 5: Preliminary, small, indirect, or not yet peer reviewed.dataset

    ELP3 shows no KMT2A-selective dependency in this project's own DepMap scan: mean Chronos -0.9203 in 11 KMT2A-rearranged lines against -1.0698 in 43 other leukaemia lines, difference +0.1495, at a pan-essentiality of -0.9647 across 1208 lines and selectivity rank 17453 of 17,728.

    DepMap CRISPR (Chronos) gene-effect scan of 11 KMT2A-rearranged versus 43 other leukaemia lines (this project's own genome-wide scan, analyses/depmap-kmt2a-selective-scan-full) · Oncofusion knowledge-graph project · analyses/depmap-kmt2a-selective-scan-full/results.json 2026
    ▸What this evidence cannot show

    Joined 2026-09-22 from analyses/depmap-kmt2a-selective-scan-full/results.json (generated 2026-09-19T10:12:06Z). NOT re-fetched and NOT independent of that scan: every caveat it carries applies, including that the 11 KMT2A-rearranged lines come from nine individuals and that the arm is myeloid-enriched, so a difference there mixes fusion status with lineage. The scan records a generation timestamp and NOT a DepMap RELEASE, which is this project's rule-83 exposure carried forward rather than fixed here. Read the numbers by this project's own DepMap rules: a rank is not an effect size, a difference is not a dependency, the anti-selective half is 50 percent of any gene set by construction with this graph's base rate at 45.3 percent, and a gene depleted this deeply across all lines is FLOOR-COMPRESSED - there is almost no dynamic range left in which selectivity could appear, so a small arm-to-arm difference is uninterpretable rather than small. The screen is also leukaemia lines only.

    ▸Evidence that argues against this (2)

    • A difference of +0.1495 at a pan-essentiality of -0.965 across 1208 lines is floor-compressed and uninterpretable, not small: a gene required in nearly every line has no dynamic range left in which KMT2A selectivity could show. Reporting the rank would be reporting the null. Oncofusion knowledge-graph project 2026
    • The one thing this number cannot be read as is a fusion dependency: the difference is +0.1495, meaning KMT2A-rearranged lines are LESS dependent on ELP3 than other leukaemia lines, which puts ELP3 at rank 17,453 of 17,728 - inside the most anti-selective 2% of the genome. At a pan-essentiality of -0.965 across 1,208 lines that is floor-compressed noise and is recorded as noise, not as an anti-dependency. It is also consistent in sign with the mouse result, in which Elongator loss is the oncogenic direction. Oncofusion knowledge-graph project 2026

• part of →ELP1 (IKBKAP/IKAP) - the Elongator scaffold that was first named for the IKK complex, is a paediatric-cancer predisposition gene, and has an RNA Pol II contact in IntAct

  catalytic subunit and scaffold of the same ELP1/2/3 lobe; UniProt records a ELP1 FD allele with reduced interaction with ELP3

• part of →ELP2 (STATIP1/StIP1) - the double beta-propeller of the Elongator core, whose informal name collides with a different human gene and whose STAT3 function is a by-similarity annotation

  both in the catalytic ELP1/2/3 lobe of Elongator

• part of →ELP4 (PAXNEB) - a required subunit of Elongator, the one partner of the seven with a genuine histone-acetyltransferase connection, and the one whose fusion supplies only its last 43 residues

  ELP3 is the catalytic subunit; ELP4 is in the accessory lobe and is required for the complex HAT activity in yeast while isolated ELP3 is not specific

• related to →NPM1::ALK (NPM-ALK), t(2;5)(p23;q35)

  ELP3 is a SUBSTRATE of a fusion oncoprotein: ALK phosphorylates ELP3 at Tyr202, ELP3 is phosphorylated in NPM-ALK-expressing tumour cells, and the Y202 mutant impairs growth and gene expression

• related to →TP53 - named in 84 entries of this graph, absent from the index genome study of the disease, and four different things depending on when you look

  mouse conditional Elp3 loss activates a p53-dependent antitumour checkpoint in haematopoiesis; p53 deletion rescues, and p53-mutant leukaemia/lymphoma then follows

• expressed in →Bone marrow haematopoietic stem cell — the postnatal comparator, and why the same fusion behaves differently here

  mouse conditional Elp3 inactivation kills committing progenitors and compromises HSC grafting - the only haematopoietic experiment in the Elongator literature

• related to →The differentiation block — what it actually is, operationally, in KMT2A::AFF1 leukaemia

  Elp3 loss kills cells specifically at the committing-progenitor stage via a p53 checkpoint - a differentiation-stage requirement, opposite in sign to a fusion-imposed block

• tests →Hypothesis: transfer-RNA and ribosome biology is a genuinely empty cell in KMT2A-rearranged leukemia, and translational capacity may be the unmeasured dependency

  ELP3 is the catalytic subunit of the tRNA wobble-modification complex that hypothesis is about, and the mouse marrow phenotype shows the axis is load-bearing in haematopoiesis

• related to →KMT2A / MLL1 — the gene that breaks

  BOUNDED ABSENCE, bounded four ways and nearly fabricated by an instrument failure: 0 literature records (ELP3[tiab] first returned 0 with an EMPTY querytranslation; true count 202), 0 of 107 IntAct records, 0 GEO leukaemia datasets, absent from all five fusion-interactome analyses here

• related to →Plain-English: what transcription elongation is, and why a traffic light explains this leukemia

  the catalytic subunit of the complex named for elongating Pol II, with a curated POLR2A interaction - but every high-resolution human structure is ELP123 bound to tRNA, with no histone in the series

• ← bindsELP5 (DERP6) - the bridge that joins ELP3 to ELP4, the most essential Elongator subunit in DepMap, and a gene whose cytoplasmic call rests on an overexpression experiment

  ELP5 directly connects ELP3 to ELP4 and is required for Elongator integrity