Oncofusion

start / graph / ptm-kmt2a-k1130-acetylation

Mechanismstrong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.q165-the-retained-acetylation-site

KMT2A K1130 acetylation - the clock-controlled, SIRT1-erased site that every KMT2A fusion retains, 17 residues from the CXXC and 208 from the breakpoint

A small chemical tag is added to one specific spot on the MLL1 protein and removed again on a daily rhythm, by an enzyme that senses how much energy the cell has. That spot sits in the part of the protein that every leukaemia fusion keeps.

The same thing, for a scientist

Acetyl-K1130 of human KMT2A (Q03164). Identified in the 2009 Choudhary global acetylome, validated with a site-specific antibody and K->R mutants in PMID 25751424, erased specifically by SIRT1 (not SIRT2/3/6/7, TSA-insensitive), rhythmic with a CT18 peak in MEFs and a ZT9 peak in mouse liver, and NAD+-responsive. Independently re-observed in PRIDE PXD009839. Position 1130 is 17 residues N-terminal to the CXXC zinc finger (1147-1195) and 208 residues N-terminal to the start of the leukaemia breakpoint cluster (exon 8, aa 1338), so it is RETAINED in every classical KMT2A fusion. The same lysine also carries ubiquitination (PXD006201), a chemically exclusive alternative.

Go deeper
Why this residue and not another

Of KMT2A's 306 lysines, 140 are retained and 10 of those carry an MS-evidenced acetylation call. Retention is not what makes K1130 interesting - 47.6% of KMT2A acetyl-lysines are retained, exactly the lysine base rate (see ana-every-ms-evidenced-kmt2a-modification-site-flagged-retained-or-lost-against-the-breakpoint).

What makes it interesting is position: 17 residues from the CXXC zinc finger, inside the region mapped as the SIRT1 contact (aa 650-1327), in the same exon (exon 5, aa 1112-1190) as the start of the CXXC. A modification 17 residues from a DNA-binding module is in a position to affect DNA binding, and nobody has tested that - the published consequence is methyltransferase activity, and the fusion has no SET domain 13.

The four things that are NOT known
  • Whether the fusion protein carries this mark. Never tested. The tryptic peptide APPIKPIKPVTR is shared between wild-type KMT2A and every KMT2A fusion, so bottom-up MS in a fusion-bearing cell cannot attribute it to one or the other.
  • Which acetyltransferase writes it. CBP/p300 acetylate MLL1, but that was shown with a pan-acetyl antibody the authors themselves describe as C-terminally biased; the site-specific antibody was never used in that experiment 1.
  • Whether it does anything other than tune SET activity. No site mutant was ever put in a catalytic assay, and the fusion has no SET domain 1.
  • Any leukaemia context at all. The source paper uses HEK293, MEFs and mouse liver - no haematopoietic cell of any kind appears in it.
Facts and figures
uniprotQ03164
position1130
residueK
modificationacetylation
writerunassigned at this residue; CBP/p300 acetylate MLL1 overall
eraserSIRT1
fusion statusRETAINED
distance to cxxc residues17
distance to breakpoint cluster residues208
exon5
within sirt1 interaction regiontrue
also modified byubiquitination (PXD006201) - chemically exclusive on the same amine
tryptic peptideAPPIKPIKPVTR
peptide distinguishes fusion from wildtypefalse
shown for fusionNO - nobody has looked in any fusion, in any partner, in any species
circadian peak mef ct18
circadian peak liver zt9
eraser negatives
[
  "SIRT2",
  "SIRT3",
  "SIRT6",
  "SIRT7",
  "class I/II HDACs (TSA-insensitive)"
]
sirt1 interaction region AA
[
  650,
  1327
]
pride deposits
[
  "PXD009839"
]
measurements
[
  {
    "quantity": "distance from acetylation site to CXXC N-terminus",
    "subject": "Q03164 K1130 to CXXC start 1147",
    "value": 17,
    "units": "residues",
    "n": 1,
    "universe": "UniProt Q03164 feature coordinates via ana-kmt2a-exon-to-domain-map",
    "null": null,
    "note": "same exon (exon 5, aa 1112-1190) as the CXXC start"
  },
  {
    "quantity": "distance from acetylation site to breakpoint cluster start",
    "subject": "Q03164 K1130 to exon 8 start 1338",
    "value": 208,
    "units": "residues",
    "n": 1,
    "universe": "Ensembl ENST00000534358 exon boundaries",
    "null": null,
    "note": "retained under every classical exon 8-14 breakpoint"
  }
]
How this could bite us back
  • The site is in shared sequence, so anything that modulates it modulates wild-type KMT2A in every cell in the body. There is no fusion-selective window here by construction.
  • SIRT1 is the eraser, and this graph already records an unresolved direction conflict over whether SIRT1 should be inhibited or activated in KMT2A-rearranged disease. Reaching for a SIRT1 tool to manipulate this site lands directly in that conflict, and SIRT1 has hundreds of other substrates including p53.
  • Manipulating a circadian-regulated site has a timing dimension no leukaemia protocol currently has. A drug that raises acetylation at CT18 and one that does so at CT6 are different experiments, and any negative result obtained at an unrecorded time of day is uninterpretable.
Still open
  1. Does acetylation at K1130 change CXXC-mediated binding of KMT2A to unmethylated CpG DNA? It is 17 residues away and nobody has asked. An EMSA or ITC comparing an acetylated and unacetylated CXXC construct extended N-terminally past 1130 is a small experiment with a clean readout.
  2. Is the KMT2A::AFF1 fusion protein acetylated at K1130 at all? Answering it requires an approach that resolves fusion from wild-type - fusion immunoprecipitation followed by MS, or a junction peptide in the same run - because the tryptic peptide is shared.
  3. Does acetylation compete with ubiquitination at this lysine, and does that set KMT2A protein half-life? Both marks are reported at K1130 and they cannot coexist.
Every source behind this entry (4)
  1. E1strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

    KMT2A is acetylated at K1130 (human numbering); the mark is erased by SIRT1 specifically, is circadian (CT18 in MEFs, ZT9 in mouse liver) and rises under EX527 and FK866 and falls under NAD+ and beta-NMN.

    NAD(+)-SIRT1 control of H3K4 trimethylation through circadian deacetylation of MLL1 · Aguilar-Arnal L, Katada S, Orozco-Solis R, Sassone-Corsi P · Nature Structural & Molecular Biology 22(4):312-8 2015
    PMID 25751424DOI
    What this evidence cannot show

    The site-level data are a custom antibody validated against K->R mutants of a fragment; there is no acetyl-mimetic and no site mutant in any catalytic assay. No haematopoietic system was used. See ana-no-acetyl-dead-or-acetyl-mimetic-kmt2a-was-ever-put-in-a-methyltransferase-assay for the full audit.

    Evidence that argues against this (1)
    • The paper's own framing is circadian biology in liver. Nothing in it addresses leukaemia, KMT2A rearrangement, or the taspase1 N-terminal fragment as a standalone species.
  2. E2established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database

    Position 1130 of UniProt Q03164 is a lysine, and the immunising peptide APPIKPIKPVTR used to raise the site-specific antibody occurs uniquely at residues 1126-1137.

    What this evidence cannot show

    Residue identity verified against the live UniProt Q03164 FASTA (3,969 aa) on 2026-09-24, not taken from a paper's text. Canonical isoform only.

    Evidence that argues against this (1)
    • Uniqueness of the 12-residue peptide was tested against Q03164 alone, not against the human proteome, so this item does not exclude the antibody recognising something else. It is also a statement about the canonical isoform only: a non-canonical cDNA behind the paper's construct would shift the numbering, and nothing in a FASTA lookup can detect that.
  3. E3moderate confidence 3 of 5: One strong study, or several smaller consistent ones.database

    Acetylation at Q03164 K1130 is independently reported in PRIDE project PXD009839, a reprocessed MS deposit that did not set out to study KMT2A.

    EBI Proteins API - proteomics-ptm, Q03164 (KMT2A) - K1130 acetylation · EMBL-EBI Proteins API / PRIDE-reprocessed MS evidence 2026
    What this evidence cannot show

    ONE deposit only - the weakest of the four Choudhary sites by deposit count. PXD009839 is a human cytomegalovirus infection acetylome in fibroblasts. Acetyl (+42.0106) and trimethyl (+42.0470) are near-isobaric on lysine and this endpoint serves no localisation probability for acetylation.

    Evidence that argues against this (1)
    • A single-deposit MS call in a virology dataset is a lead, not an established site. If it is a misassignment, the residue this whole line of work is named after is the least supported of the four.
  4. E4established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paper

    The site was originally identified not in the 2015 circadian paper but in the 2009 Choudhary global acetylome.

    Lysine acetylation targets protein complexes and co-regulates major cellular functions · Choudhary C, Kumar C, Gnad F, Nielsen ML, Rehman M, Walther TC, Olsen JV, Mann M · Science 325(5942):834-40 2009
    PMID 19608861DOI
    What this evidence cannot show

    ABSTRACT ONLY - the full text and supplementary tables are behind a 403 at science.org. Whether the KMT2A peptide came from the MV4-11 arm of its cell panel is unresolved; see ana-the-founding-acetylome-that-discovered-the-kmt2a-site-was-run-in-a-panel-containing-mv4-11-a-kmt2a-aff1-line.

    Evidence that argues against this (1)
    • Priority claims cannot be supported from an abstract. This item asserts the site was FIRST identified in 2009; the abstract establishes only that a large acetylome existed and reported 3,600 sites. Whether KMT2A was among them is not in the abstract, and whether something earlier reported it was not searched for. The safe version of this claim is the narrow one - that the 2015 paper credits the 2009 study rather than claiming the mapping itself - and the entry should be read that way.
Connected to