Oncofusion

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Non-codingstrong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.Q35-ptefb-reservoir

RN7SK / 7SK snRNA - the 332-nucleotide brake on elongation, and the one molecule in this beat that every dataset this project uses is blind to

also called RN7SK · 7SK · 7SK snRNA · 7SK RNA

7SK is a short RNA that does not code for a protein; its job is to hold the elongation enzyme P-TEFb in an off state until a cell needs it. It is the brake on the exact machine KMT2A::AFF1 is supposed to jam open, and it is invisible to ordinary RNA sequencing, which is one reason nobody has measured it in these leukaemias.

The same thing, for a scientist

RN7SK (HGNC:10037, ENSG00000283293, NCBI Gene 125050) is a 332-nucleotide RNA polymerase III transcript at chr6:52,995,621-52,995,948 on the plus strand of GRCh38, with RefSeq NR_001445.2 ending in the 3' U-rich stretch that LARP7 binds [E1]. It is the scaffold of the 7SK snRNP. In HeLa cells more than half of all nuclear P-TEFb is held in a 7SK-containing particle with very weak kinase activity, and inhibiting transcription or irradiating the cells disrupts the particle and raises CDK9 activity [E2]. 7SK binding alone does not inhibit P-TEFb; the RNA acts as the adapter that lets HEXIM1 reach and inhibit the kinase [E3]. Because 7SK is not polyadenylated, it does not appear in poly-A RNA-seq: it returns **zero rows in the entire 24.3-million-row Human Protein Atlas cell-line table across 1,206 lines** [E4]. Every RNA-layer claim in this graph rests on poly-A data, so the abundance of the brake in KMT2A-rearranged blasts is not merely unmeasured but unmeasurable by the instruments already in use.

Go deeper
Why it is filed as a noncoding_element and not a gene

HGNC classes RN7SK as non-coding RNA (locus type 'RNA, long non-coding'), Ensembl gives its biotype as snRNA, and it is transcribed by Pol III from a type 3 external promoter rather than by Pol II 1. This graph files ncRNAs as noncoding-* with type noncoding_element (see noncoding-hottip, noncoding-hotairm1), so gene-rn7sk would have been the wrong id. Anyone writing an edge to this entry should use noncoding-rn7sk.

The measurement gap, stated precisely

A poly-A-selected library cannot see a Pol III transcript that is not polyadenylated. The check was run directly: filtering HPA's rna_celline.tsv for any gene name containing 7SK or starting RN7S over all 24,315,372 rows returns nothing at all 4. The same applies to DepMap's expression matrix and to essentially every published RNA-seq dataset in KMT2A-rearranged leukaemia, because they are poly-A libraries.

This is not a complaint about data quality. It is the reason the reservoir has never been examined in this disease, and it tells you what a study would have to do: total RNA with rRNA depletion, or a Northern blot, or RT-qPCR with a 7SK-specific primer pair, or - better, because it measures the partition rather than the abundance - glycerol-gradient fractionation followed by immunoprecipitation. That experiment is written up as exp-glycerol-gradient-ptefb-partition-kmt2a-aff1.

Structure, briefly and with the limit stated

7SK folds into four stem-loops. Stem-loop 1 carries the apical region that HEXIM1 and HIV-1 Tat bind competitively, and a structure-based study of HEXIM, Tat-G and Tat-Fin arginine-rich motifs bound to the 7SK apical stem-loop 1 shows that HEXIM binding locally destabilises the RNA in a way Tat then exploits to displace it 5. No structure of the complete 7SK snRNP with P-TEFb bound exists, and none of the structural work has been done in a leukaemia context.

Facts and figures
element symbolRN7SK
classsnRNA (Pol III type 3 promoter)
genome buildGRCh38
chromosome6
start52995621
end52995948
strand+
cytoband6p12.2
locuschr6:52,995,621-52,995,948
ensembl gene IDENSG00000283293
ensembl canonical transcriptENST00000636484
hgnc IDHGNC:10037
entrez ID125050
refseqNR_001445.2
length nt332
ID resolution noteHGNC REST returned symbol RN7SK, name 'RNA component of 7SK nuclear ribonucleoprotein', alias 7SK; Ensembl lookup of ENSG00000283293 returned display_name RN7SK on GRCh38; RefSeq NR_001445.2 fetched as FASTA and measured at 332 nt. An Open Targets search for RN7SK also returns ENSG00000202198 labelled '7SK' (misc_RNA) and numerous RN7SKP pseudogenes - do not use those.
detectable in polyA rnaseqfalse
measurement routetotal RNA with rRNA depletion, Northern blot, 7SK-specific RT-qPCR, or glycerol-gradient fractionation with immunoprecipitation
direction of change in kmt2a runknown - never measured
protein partners
[
  "MEPCE (5' methylphosphate cap)",
  "LARP7 (3' U-rich end)",
  "HEXIM1",
  "HEXIM2",
  "CDK9",
  "CCNT1",
  "AFF1 (via P-TEFb)",
  "hnRNP A1/A2/Q/R"
]
related entries
[
  "protein-7sk-snrnp",
  "gene-hexim1",
  "gene-larp7",
  "gene-mepce",
  "gene-cdk9"
]
Still open
  1. What is the absolute 7SK copy number per nucleus in a KMT2A-rearranged blast, and how does it compare with P-TEFb copy number? Nobody has counted either.
  2. Do the RN7SK pseudogenes produce any transcript in leukaemia, and would a short-read study mis-assign it to the parent locus?
  3. Is 7SK itself a chromatin-associated RNA at KMT2A fusion target genes, as the 7SK-BAF and KAP1 literature suggests for other loci? No 7SK CHART or ChIRP exists in any KMT2A-rearranged cell.
Every source behind this entry (5)
  1. E1established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database

    RN7SK is HGNC:10037 / ENSG00000283293 / NCBI Gene 125050, located at chr6:52,995,621-52,995,948 on the plus strand of GRCh38, with RefSeq NR_001445.2 measured at 332 nucleotides ending in a run of uridines.

    What this evidence cannot show

    HGNC gives the cytogenetic location as 6p12.2 and the locus type as 'RNA, long non-coding' while Ensembl gives the biotype as snRNA; the two disagree on nomenclature, not on position. The Ensembl span is 328 bp against a 332 nt RefSeq, a four-base end discrepancy that is typical for Pol III transcript annotation and is not resolved here. The human genome also carries many RN7SK pseudogenes, so any read-mapping study must handle multi-mapping explicitly.

    Evidence that argues against this (1)
    • Database records are opposable on scope: an accession and a coordinate say where the gene is, not how much of its product is present in any cell. Nothing in this record bears on abundance in leukaemia. HGNC; Ensembl; NCBI RefSeq 2026
  2. E2established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paper

    In HeLa cells more than half of P-TEFb is sequestered in larger complexes containing 7SK RNA that show very weak kinase activity, and chemical inhibition of transcription or ultraviolet irradiation completely disrupts the P-TEFb/7SK complex and enhances CDK9 activity.

    7SK small nuclear RNA binds to and inhibits the activity of CDK9/cyclin T complexes. · Nguyen VT, Kiss T, Michels AA, Bensaude O · Nature 2001
    PMID 11713533DOI
    What this evidence cannot show

    HeLa cells only, measured by gradient fractionation and in vitro kinase assays in 2001. 'More than half' is the authors' phrasing and is not resolved to a percentage. No haematopoietic cell, and no leukaemia.

    Evidence that argues against this (1)
    • The independent paper published alongside it frames the same reservoir as a control point for HIV-1 Tat transactivation rather than as a general growth switch, and shows the inhibition acts both by blocking CDK9 catalysis and by preventing recruitment to the promoter - two mechanisms with different consequences for a chromatin-tethered fusion. Yang Z et al. 2001
  3. E3established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paper

    7SK binding alone is not sufficient to inhibit P-TEFb; inhibition requires HEXIM1, and 7SK acts as the adapter that mediates the HEXIM1:P-TEFb interaction.

    PMID 14580347DOI
    What this evidence cannot show

    Biochemistry in HeLa extracts and in vitro. The corollary matters for any intervention: raising 7SK without HEXIM protein would not brake elongation.

    Evidence that argues against this (1)
    • A later reconstitution finds the 7SK-P-TEFb interaction can occur independently of HEXIM1 and is governed by CDK9 T-loop phosphorylation, so the order of assembly is not simply HEXIM-first. Chen R et al. 2004
  4. E4established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database

    RN7SK returns zero rows in the Human Protein Atlas cell-line RNA table (24,315,372 rows, 1,206 cell lines), as does any gene name beginning RN7S, because the library is poly-A selected and 7SK is a non-polyadenylated Pol III transcript.

    What this evidence cannot show

    This is an absence in one resource. It is bounded by the exact filter run - any 'Gene name' containing the string 7SK or starting RN7S - and it generalises to poly-A libraries in principle rather than by having been checked in every dataset. It says nothing about whether 7SK is present in these cells; it says the instrument cannot see it.

    Evidence that argues against this (1)
    • A counted absence is only as good as the symbol set. The filter used the current HGNC symbol and a prefix wildcard; a dataset that annotated the locus under the alias 7SK alone would still have matched, but one annotating it only by an RNAcentral or Rfam identifier would not. HGNC; Ensembl; NCBI RefSeq 2026
  5. E5strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

    Structures of HEXIM, TatG and TatFin arginine-rich motifs bound to the apical stem-loop 1 of 7SK show that HEXIM primes its own displacement by locally destabilising the RNA, and that Tat exploits that destabilisation to bind 7SK more efficiently.

    A structure-based mechanism for displacement of the HEXIM adapter from 7SK small nuclear RNA. · Pham VV, Gao M, Meagher JL, Smith JL, D'Souza VM · Commun Biol 2022
    PMID 35970937DOI
    What this evidence cannot show

    NMR and crystallographic structures of isolated arginine-rich motifs with an RNA stem-loop, not of the assembled snRNP, and the displacing factor studied is a viral protein. No cellular leukaemia experiment.

    Evidence that argues against this (1)
    • A displacement mechanism worked out for a viral arginine-rich motif need not be the mechanism cells use; the SEC-based route described in `mechanism-sec-condensates-extract-ptefb-from-the-reservoir` does not require a protein that binds 7SK RNA at all. Guo C et al. 2020
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