TPR / Megator (P12270) - the nuclear-basket nucleoporin that builds heterochromatin exclusion zones, in the pan-MLL-fusion core
also called TPR · Megator · translocated promoter region · NPC-associated intranuclear protein · nucleoprotein TPR
TPR is the long coiled-coil protein that forms the basket hanging from the nuclear side of every nuclear pore, and it keeps condensed chromatin away from the pores so that genes near them stay reachable. It co-purifies with all seven MLL fusions tested, which - if it is real - would place the fusion at the nuclear periphery, an address nobody has looked for.
The same thing, for a scientist
TPR (P12270, 2,363 aa) is the architectural element of the nuclear pore complex basket. RNAi removal of TPR, or of its large coiled-coil domain, abolishes the heterochromatin exclusion zones that normally gap the nuclear envelope at pores, letting condensing chromatin cover the NPCs - so TPR actively defines a nuclear sub-compartment at the periphery. In Skucha 2018 it co-purified with all seven MLL fusions, MLL-AF4 (= KMT2A::AFF1) at p = 0.0258 with 12|7 spectra and a clean 0|0 negative control, with MLL-AF9 at 5.03e-4 (45|35). This graph already carries localization-nuclear-lamina-lads-kmt2a-r, which is about the peripheral compartment TPR excludes heterochromatin from, and a large NUP98-fusion beat - nucleoporin biology is not foreign to this project. It is also a live symbol trap: `TPR` in the literature overwhelmingly means the tetratricopeptide repeat, and the only two records returned by a TPR-plus-KMT2A query are a UTX tetratricopeptide-repeat mutation paper and a treadmill-walking study in older adults.
The Skucha row
7 of 7 fusions. MLL-AF1p 4.78e-4 (26|15), MLL-AF4 0.0258 (12|7), MLL-AF9 5.03e-4 (45|35), MLL-CBP 0.0162 (12|12), MLL-EEN 0.00132 (42|39), MLL-ENL 9.2e-4 (33|35), MLL-GAS7 0.017 (25|20); negative control 0|0 1. Substantial spectral depth at every bait - 12 to 45 per replicate - and a clean control. On raw depth this is among the better-supported proteins in the set, though the MLL-AF4 p-value is middling.
TPR builds a subnuclear compartment, which is why this row is on the PI's priority list
Heterochromatin in somatic cells piles against the nuclear envelope but is interrupted by channel- and cone-shaped zones at the nuclear pores. Those heterochromatin exclusion zones depend on TPR and on its large coiled-coil-forming domain: RNAi loss of TPR lets condensing chromatin cover the whole nuclear surface, including the pores 2. So TPR is not merely resident at a structure - it creates a chromatin-free sub-compartment. If a KMT2A fusion were recovered there, that would be a specific, testable statement about where the fusion works, and this graph's localization-nuclear-lamina-lads-kmt2a-r entry is the natural place for it to connect.
Analogous biology: nucleoporins are already a fusion family here
This project holds a substantial NUP98-fusion beat - NUP98-NSD1, NUP98-KDM5A, NUP98-HOXA9, NUP98-HOXD13, NUP98-DDX10 - and a SET::NUP214 beat. In those, a nucleoporin's FG repeats become part of an oncoprotein and its condensate behaviour drives the leukaemic programme. TPR is a different nucleoporin in a different position (basket rather than channel FG mesh) and is here as a partner rather than as a fusion component, so the analogy is structural, not mechanistic. It is recorded so that the two are not conflated: nothing about NUP98-fusion biology supports a claim about TPR binding KMT2A::AFF1.
The symbol trap, which is the reason the counted absence is interpretable
TPR[tiab] AND (KMT2A[tiab] OR MLL[tiab] OR "MLL-AF4"[tiab] OR "MLL-AF9"[tiab]) returns 2 records and neither is about this protein: PMID 32071397 concerns cancer-derived UTX TPR mutations G137V and D336G - TPR there is the tetratricopeptide repeat domain of KDM6A - and PMID 23170753 is a cardiovascular study of downhill treadmill walking in older adults. The alias Megator[tiab] AND (KMT2A[tiab] OR MLL[tiab]) returns 0. The token TPR is unusable as a gene search term without title-checking every hit, and TPR appears in 24 node files of this graph, almost all of them meaning the repeat rather than the nucleoporin. data/symbol-collisions.json has a UTX/KDM6A row whose text happens to contain the string TPR, but no row for TPR itself as of 2026-09-21.
| uniprot | P12270 |
|---|---|
| length AA | 2363 |
| accession resolution | Resolved live 2026-09-21: gene_exact:TPR AND organism_id:9606 AND reviewed:true returns exactly one row, gene_primary TPR, P12270, TPR_HUMAN, 2,363 aa, no gene synonyms listed. Matches Skucha's table. The gene-symbol lookup is clean; it is the LITERATURE token that collides (see symbol_collision). |
| localization | Nucleus - nuclear envelope and nuclear pore complex, with cytoplasmic, spindle and kinetochore pools during mitosis |
| subnuclear localization | NUCLEAR PORE COMPLEX, nuclear basket - and TPR defines the heterochromatin exclusion zone immediately around each pore, which is itself a distinct nuclear sub-compartment. |
| localization evidence | UniProt P12270, fetched 2026-09-21, is the most heavily evidenced localisation record of the twelve: 'Nucleus, nuclear pore complex' with NINE ECO:0000269 experimental citations, 'Nucleus membrane' with nine more across two comments, 'Nucleus envelope' with two, 'Cytoplasm' with two, 'Cytoplasm, cytoskeleton, spindle' with one and 'Chromosome, centromere, kinetochore' with one. |
| shown for fusion | KMT2A::AFF1 (MLL-AF4) by co-purification at p = 0.0258, plus all six other Skucha baits with 12 to 45 spectra each. NO independent experiment ties TPR to a KMT2A fusion in any system. |
| symbol collision | TPR the gene symbol collides with TPR the tetratricopeptide repeat, which is far commoner in the literature and appears inside protein and domain names. Both of the two records returned by the gene-symbol query are false positives, and 24 node files in this graph contain the string TPR, almost all meaning the repeat. data/symbol-collisions.json contains a UTX/KDM6A row whose free text includes the string TPR, but NO row for TPR itself as of 2026-09-21; reported to the coordinator rather than added, because this beat does not own that file. |
| graph context | This graph has a substantial nucleoporin presence - fusion-nup98-nsd1, fusion-nup98-kdm5a, fusion-nup98-hoxa9, fusion-nup98-hoxd13, fusion-nup98-ddx10 and a SET::NUP214 beat - and localization-nuclear-lamina-lads-kmt2a-r covers the peripheral chromatin compartment. There was no entry for TPR, and no entry treating a nucleoporin as a KMT2A-fusion partner rather than as a fusion component. |
skucha 2018
{
"bait": "MLL-AF4 (= KMT2A::AFF1)",
"p_value": 0.0258,
"spectral_counts": "12|7",
"n_fusions_of_seven": 7,
"negative_control_counts": "0|0",
"per_bait": {
"MLL-AF1p": "0.000478 (26|15)",
"MLL-AF4": "0.0258 (12|7)",
"MLL-AF9": "0.000503 (45|35)",
"MLL-CBP": "0.0162 (12|12)",
"MLL-EEN": "0.00132 (42|39)",
"MLL-ENL": "0.00092 (33|35)",
"MLL-GAS7": "0.017 (25|20)"
},
"source": "analyses/skucha-mll-fusion-interactome/results.json, re-derived from the cached MOESM4 xlsx on 2026-09-21"
}cell types and states
[ "Jurkat (human T-ALL) - AP-MS host, nuclear lysate", "cultured human cells with poliovirus-induced chromatin condensation - heterochromatin exclusion zones", "senescent fibroblasts - pore density and heterochromatin reorganisation", "no KMT2A-rearranged cell of any kind" ]
bounded literature
{
"query": "TPR[tiab] AND (KMT2A[tiab] OR MLL[tiab] OR \"MLL-AF4\"[tiab] OR \"MLL-AF9\"[tiab])",
"querytranslation": "\"TPR\"[Title/Abstract] AND (\"KMT2A\"[Title/Abstract] OR \"MLL\"[Title/Abstract] OR \"MLL-AF4\"[Title/Abstract] OR \"MLL-AF9\"[Title/Abstract])",
"count": 2,
"on_topic_after_title_check": 0,
"rejected": "PMID 32071397 - 'Cancer-derived UTX TPR mutations G137V and D336G impair interaction with MLL3/4 complexes and affect UTX subcellular localization' - where TPR is the TETRATRICOPEPTIDE REPEAT of KDM6A, not this gene. PMID 23170753 - cardiovascular responses during downhill treadmill walking in older adults.",
"alias_query": "Megator[tiab] AND (KMT2A[tiab] OR MLL[tiab]) returns 0; querytranslation \"Megator\"[Title/Abstract] AND (\"KMT2A\"[Title/Abstract] OR \"MLL\"[Title/Abstract])",
"names_tried": [
"TPR",
"Megator"
],
"date": "2026-09-21",
"tool": "NCBI esearch db=pubmed",
"positive_control": "the identical query shape with MEN1 returns 85",
"bound": "Titles and abstracts only; supporting figures not searched. 'Nucleoporin TPR' as a phrase was not run and would be the precise form to try next."
}functionally screened in the source paper
{
"_added": "king, cycle 48, 2026-09-21, after Q86 flagged that cycle-47 entries understate the record. Verified by me directly from the supplementary file, not from the paper's prose.",
"screened": true,
"library_symbol": "TPR",
"shrnas_for_this_gene": 6,
"design": "Supplementary Table 6 / MOESM5 is 768 data rows, 128 unique gene symbols, EXACTLY 6 shRNAs each -- counted with openpyxl on 2026-09-21. Negative-selection RNAi screen in MLL-AF9-expressing MOLM-13.",
"what_this_DOES_establish": "Every one of the 128 conserved MLL-fusion interactors, this protein included, was functionally tested against an MLL fusion. An entry saying 'nothing in the paper validates this prey' is true of BINDING and understates the record.",
"what_this_does_NOT_establish": "A per-gene result. Scores are presented as heatmaps (Fig. 2c/2d) and no per-gene depletion value is tabulated, so for any individual gene the outcome is measured-not-reported. It is also MLL-AF9 MOLM-13, a myeloid line, not the index fusion and not B-lineage.",
"absence_class_for_the_per_gene_score": "measured-not-reported"
}- TPR is required for nuclear pore basket architecture, mRNA export quality control and the spindle assembly checkpoint. Perturbing it is a whole-cell intervention with mitotic consequences, not a targeted one.
- A co-purification of a nuclear-envelope protein from a nuclear lysate has an obvious artefactual route - envelope fragments - and the honest prior is that this row is background until an imaging or proximity-labelling experiment says otherwise.
- If a peripheral pool of the fusion exists and is the transcriptionally active one, then therapies that measure bulk fusion occupancy would be blind to the compartment that matters.
- Does KMT2A::AFF1 have a nuclear-periphery pool? Two-colour imaging against TPR or NUP153 in a t(4;11) line would answer a question this graph has never asked, and the Skucha row is the first reason to ask it.
- Are other nucleoporins - NUP153, NUP98, NUP214, the Y-complex - in the Skucha 960-protein network? A pore-wide signature would most likely mean nuclear-envelope carry-over in the lysate rather than a contact, and that is the cheapest way to kill this row.
- Are KMT2A::AFF1 target genes positioned at or away from nuclear pores? Pore-proximal positioning is associated with active transcription, which would make a peripheral pool mechanistically interesting rather than incidental.
- Does the fusion interact with TPR's coiled-coil domain - the part that builds the exclusion zone - or with the basket's other faces?
- E1moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper
TPR co-purified with all seven Strep-HA-tagged MLL fusions in isogenic Jurkat cells, with the MLL-AF4 (= KMT2A::AFF1) call at p = 0.0258 and 12|7 spectral counts, and MLL-AF9 at p = 5.03e-4 with 45|35, against a 0|0 negative control.
MLL-fusion-driven leukemia requires SETD2 to safeguard genomic integrity. · Skucha A, Ebner J, Schmoellerl J, Roth M, Eder T, Cesar-Razquin A, Stukalov A, Vittori S, Muhar M, Lu B, Aichinger M, Jude J, Mueller AC, Gyorffy B, Vakoc CR, Valent P, Bennett KL, Zuber J, Superti-Furga G, Grebien F · Nature Communications 2018What this evidence cannot show
SYSTEM: the AP-MS host is JURKAT, a T-ALL line, whereas KMT2A::AFF1 disease is B-lineage infant leukaemia, so a partner that needs a B-cell or infant proteome cannot appear here and a T-lineage partner can appear spuriously. The bait is a Strep-HA-tagged, SINGLE-COPY, doxycycline-INDUCED transgene, not the endogenous fusion. Prey was recovered from bulk nuclear lysate, so co-purification is not evidence of a direct contact. INCLUSION RULE: the paper kept the top 300 interactions per bait by combined p-value rather than applying a p threshold (Methods, verbatim: "The 300 most significant interactions per bait were retained"). Measured by this beat by reading the cached Supplementary Table 5 xlsx directly on 2026-09-21: 545 of the 2,049 per-bait p-values in the table (26.6%) exceed 0.05, to a maximum of 0.175. This graph's own king analysis ana-the-index-fusion-interactome-is-not-distinctive-and-two-earlier-answers-were-artifacts found the MLL-AF4 column reaches deepest into the weak tail of the seven, so an MLL-AF4 p-value is systematically weaker than the same protein's p-value under another bait and should not be read as a weaker interaction. TPR is a 2,363-residue coiled-coil protein and large coiled-coil proteins are frequent affinity-purification background; the clean 0|0 control argues against that here but does not settle it. Nuclear lysate preparation shears the nuclear envelope, so recovery of a pore-basket protein in a nuclear lysate purification has an obvious non-specific route. Values re-read from the cached xlsx on 2026-09-21.
Evidence that argues against this (1)
- IntAct has never curated this dataset (pubid:29777171 returns 0 rows against a working positive control), so no independent curator has re-examined these calls, and the raw data at ProteomeXchange PXD009338 have not been reanalysed here. Nothing in the paper validates this particular prey by an orthogonal assay: of the twelve proteins in this beat, only SETD2 is mentioned anywhere in the paper's body text (counted by regex over the PMC full text, 2026-09-21; SF3A3 appears once, as a named non-selective control). ProteomeXchange/PRIDE 2018
- E2strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
The nucleoporin TPR is required to establish nuclear-pore-associated zones of heterochromatin exclusion: RNAi loss of TPR, or of its large coiled-coil domain, allows condensing chromatin to cover the whole nuclear surface including the nuclear pore complexes, so TPR directly forms a morphologically distinct nuclear sub-compartment and delimits heterochromatin distribution.
Protein Tpr is required for establishing nuclear pore-associated zones of heterochromatin exclusion. · Krull S, Dorries J, Boysen B, Reidenbach S, Magnius L, et al. · EMBO J 2010What this evidence cannot show
A cell-culture model in which chromatin condensation was induced by poliovirus infection to make the exclusion zones visible - an induced, non-physiological condensation state, though the authors report the zones resemble those in normal tissue cells. Not a haematopoietic or fusion system. Read from the abstract.
Evidence that argues against this (1)
- Nuclear pore density itself reorganises heterochromatin during senescence, so the causal arrow between TPR, pores and heterochromatin is not one-way. Boumendil C et al. 2019
- E3strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
Nuclear pore density controls heterochromatin reorganisation, establishing that the pore-associated compartment is an active determinant of chromatin architecture rather than a passive boundary.
Nuclear pore density controls heterochromatin reorganization during senescence. · Boumendil C, Hari P, Olsen KCF, Acosta JC, Bickmore WA · Genes Dev 2019What this evidence cannot show
Oncogene-induced senescence in fibroblasts, not leukaemia and not a fusion; read from the title and search metadata rather than the full text, and the specific role of TPR within that mechanism was not verified here. Cited to bound E2 rather than to assert anything about the index disease.
Evidence that argues against this (1)
- Senescence is a state with wholesale nuclear reorganisation; a mechanism established there may not operate in a proliferating blast. Krull S et al. 2010
Removes the cheapest explanation without promoting the protein: a nuclear-envelope carry-over account predicts the pore complex arriving broadly, and nucleoporins are the weakest chromatin-adjacent row here at 5 of 27 against 1.30 expected.
co-purified with MLL-AF4 at p=0.0258 (12|7 spectra, 0|0 control); a nuclear-envelope protein in a nuclear lysate, so carry-over is the leading alternative
- related to →The nuclear lamina and lamina-associated domains - evidence grade for KMT2A: weak and indirect, not none
TPR builds the heterochromatin exclusion zones that gap the lamina-associated peripheral chromatin at every nuclear pore
- analogous to →NUP98::NSD1, t(5;11)(q35;p15.5)
nucleoporin biology in leukaemia - but TPR appears here as a partner of the fusion, not as a fusion component, so the analogy is structural and not mechanistic
pan-fusion Skucha interactor with no gene entry before cycle 47
- ← co-occurs withNUP50 / Npap60 (Q9UKX7) - a MOBILE nuclear-basket nucleoporin in the pan-MLL-fusion core, and the evidence says basket, not nuclear envelope
the two pan-fusion nuclear-basket nucleoporins; no FG central-channel nup is in the network at any n
KPNA2, NUP50, TPR and NUP153 are the only transport-related proteins in the 960; no importin-beta, no Ran