KMT2A K1130 ubiquitination - the same retained lysine as the clock acetylation site, carrying a chemically exclusive second mark that no KMT2A paper has ever mentioned
The exact spot on MLL1 that carries a daily on/off chemical tag can also carry a completely different tag - one that usually marks proteins for destruction. The two cannot be there at once, so the spot is a switch rather than a dial. No paper about MLL1 has ever said this.
The same thing, for a scientist
UniProt Q03164 K1130 is reported as a ubiquitination site in PRIDE PXD006201 (UbiSite, ~62,000 sites across two human cell lines) in addition to being the acetylation site of PMID 25751424. Acetylation and ubiquitination both occupy the lysine epsilon-amine and are mutually exclusive, so a lysine carrying both is a competitive switch. K1130 is one of only three retained KMT2A lysines with both marks (K277, K326, K1130). The finding is database-derived, rests on a single deposit, and has no functional support of any kind - it is a lead with a mechanism, not a result.
Why a dual-modified lysine is worth its own entry
Acetylation neutralises the lysine's positive charge; ubiquitination covalently attaches an 8.5 kDa protein through the same amine. They compete for one chemical position. A site carrying both is, mechanistically, a switch between two fates for the protein - and this graph already holds mechanism-acetylation-is-a-cycle-not-a-mark, which argues exactly that acetylation must be read as a cycle with a writer and an eraser rather than as a static mark. A competing ubiquitination adds a third arm to that cycle.
The hypothesis this generates, for free, from a database: acetylation at K1130 protects KMT2A from ubiquitination at K1130, and SIRT1 deacetylation licenses it. If true, the circadian acetylation rhythm would impose a circadian rhythm on KMT2A protein stability, and it would do so in the retained portion - which the fusion also has. Nothing here tests it.
The three retained dual-modified lysines
| lysine | acetylation deposits | ubiquitination deposits | fusion status |
|---|---|---|---|
| K277 | PXD005252 | PXD019854, PXD023889, PXD027328 | RETAINED |
| K326 | PXD005252, PXD009994 | PXD027328 | RETAINED |
| K1130 | PXD009839 | PXD006201 | RETAINED |
(A fourth dual-modified lysine, K3804, carries SUMOylation and ubiquitination and is LOST.) 1
| uniprot | Q03164 |
|---|---|
| position | 1130 |
| residue | K |
| modification | ubiquitination |
| writer | unknown |
| eraser | unknown |
| fusion status | RETAINED |
| competes with | acetylation at the same lysine (PMID 25751424, PXD009839) |
| shown for fusion | NO - nobody has looked in any fusion |
| novel to this graph | true |
pride deposits
[ "PXD006201" ]
retained dual modified lysines
{
"K277": [
"acetylation",
"ubiquitination"
],
"K326": [
"acetylation",
"ubiquitination"
],
"K1130": [
"acetylation",
"ubiquitination"
]
}measurements
[
{
"quantity": "retained KMT2A lysines carrying both acetylation and ubiquitination calls",
"subject": "Q03164 aa 1-1337",
"value": 3,
"units": "lysines",
"n": 140,
"universe": "140 retained lysines in Q03164",
"null": null,
"note": "K277, K326, K1130. No null was computed for whether 3 exceeds chance given 10 retained acetyl and 5 retained ubiquitin calls - and the naive expectation (10*5/140 = 0.36) suggests it might, but that calculation assumes independence between two detectability-biased assays and should not be quoted."
}
]- If ubiquitination at K1130 degrades KMT2A, then an intervention raising acetylation there would STABILISE KMT2A - including the wild-type allele, whose retention this disease depends on. Stabilising the wild-type protein is not obviously the direction anyone wants, and it is the opposite of what a naive reading of 'block the degradation signal' would suggest.
- This is a single-deposit database observation with no functional data and one published result arguing against its most obvious consequence. It is exactly the kind of finding that becomes a grant aim before anyone checks it.
- Does acetylation at K1130 block ubiquitination at K1130? A K1130R mutant, an acetyl-mimetic, or simply a SIRT1 inhibitor followed by a ubiquitin-remnant MS run would answer it, and none has been done.
- Is KMT2A protein half-life circadian? If the acetyl/ubiquitin switch at K1130 is real and SIRT1-driven, KMT2A abundance should oscillate - and the source paper explicitly reports that it does NOT (Suppl Fig 5d: 'MLL1 protein levels are not regulated by SIRT1 and remain constant during the circadian cycle'). That is a published result pointing AGAINST the degradation hypothesis, in mouse liver, and it should be the first thing anyone pursuing this reads.
- Is the co-occurrence of acetylation and ubiquitination at 3 of 140 retained lysines more than the two assays' detectability biases would produce? The naive independence calculation says yes and the naive calculation is not trustworthy here.
- E1moderate confidence 3 of 5: One strong study, or several smaller consistent ones.database
Q03164 K1130 is reported as a ubiquitination site in PRIDE PXD006201, and is one of three retained KMT2A lysines carrying both an acetylation and a ubiquitination call.
EBI Proteins API - proteomics-ptm, Q03164 (KMT2A) - K1130 ubiquitinylation · EMBL-EBI Proteins API / PRIDE-reprocessed MS evidence 2026What this evidence cannot show
ONE deposit. Ubiquitination site identification by the UbiSite antibody approach captures the remnant on the modified lysine; misassignment within a peptide is possible and no localisation probability is served for ubiquitinylation by this endpoint. Crucially, the acetylation call and the ubiquitination call come from DIFFERENT experiments in DIFFERENT cells, so nothing shows the two marks compete - only that both have been seen at that position.
Evidence that argues against this (1)
- Lysines that appear in large-scale ubiquitinome studies are enriched for surface-exposed, disordered positions, and so are lysines that appear in acetylome studies. Co-occurrence of the two marks at one position may reflect shared detectability bias rather than shared biology. A proper test would ask whether dual-modified lysines are more common than the product of the two marginal rates, and that test was not run.
- E2established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.dataset
PXD006201 is the UbiSite study, an immunoaffinity method reporting ~62,000 unique ubiquitination sites across two human cell lines.
PRIDE Archive PXD006201 - Characterisation of protein ubiquitination using UbiSite technology · PRIDE Archive, EMBL-EBI 2026What this evidence cannot show
The PRIDE record declares cell types as 'Blood' and 'Larynx squamous cell carcinoma cell line' without naming the lines. Neither is a KMT2A-rearranged line as declared.
Evidence that argues against this (1)
- A method reporting ~62,000 sites carries a large absolute false-discovery burden even at a well-controlled 1% FDR - on the order of 600 wrong sites - and this entry rests on exactly one of the 62,000. The description quoted is also the depositors' own abstract as lodged with PRIDE, not an independent assessment of the method, so it cannot speak to how well the method performs on a low-abundance chromatin scaffold like KMT2A.
- E3established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database
Position 1130 of Q03164 is a lysine.
UniProtKB Q03164 (KMT2A_HUMAN) canonical sequence · UniProt 2026What this evidence cannot show
Residue identity verified against the live UniProt Q03164 FASTA (3,969 aa) on 2026-09-24. Canonical isoform only.
Evidence that argues against this (1)
- This item is true and nearly beside the point, which is its weakness. The question that decides the entry is not whether 1130 is a lysine but whether the ubiquitin remnant was localised to it rather than to a neighbour. K1133 is three residues away in the same tryptic peptide, and the EBI endpoint serves no localisation probability for ubiquitinylation. A confident residue call here would need the deposit's own site-localisation scores, which were not retrieved.
chemically exclusive on the same lysine epsilon-amine - one mark excludes the other
- part of →KMT2A / MLL1 — the gene that breaks
Q03164 K1130 ubiquitination, retained
a third arm to the cycle: a competing ubiquitination at the same position
one of 5 retained ubiquitination sites