DNA damage raises menin levels through ATM/ATR phosphorylation, and the residue has never been mapped
also called MEN1 ATM phosphorylation · menin DNA damage stabilisation
After DNA damage, menin protein levels go up, and the reason given is that the damage-sensing enzymes ATM and ATR put phosphate on it. Which spot they use has never been identified.
The same thing, for a scientist
In melanocytes, **MEN1 levels increase after DNA damage as a result of phosphorylation by the DNA damage kinase ATM/ATR**, and menin then drives transcription of BRCA1, RAD51 and RAD51AP1 to support homologous recombination, recruited to those promoters by ESR1 together with the MLL methyltransferase. This is a second kinase input on the drug target, in the same DNA-damage-response family as the ATR-KMT2A S516 switch, and it runs in the **opposite direction** from the PKA switch: ATM/ATR **stabilises** menin, PKA **sequesters** it. **No residue is named anywhere we could read.** The only observed MEN1 phosphosites in public proteomics are S487, S543, S593 and T594, and none is attributed to ATM/ATR. The entry exists to record a real kinase-menin link and to mark precisely how unmapped it is.
What is claimed and what is missing
Claimed 1: MEN1 levels rise after DNA damage; the rise is attributed to phosphorylation by ATM/ATR; menin then transactivates HR genes with MLL as coactivator, recruited by ESR1, with increased H3K4me3 at BRCA1, RAD51 and RAD51AP1 promoters.
Missing: the residue. The abstract names no site, and the full text could not be read - Europe PMC fullTextXML returned HTTP 500 for PMC3700119 and efetch db=pmc returned a record with no body element. So this beat cannot say which serine or threonine is involved, whether it is S/T-Q (the ATM/ATR consensus), or whether the phosphorylation is direct.
A checkable prediction follows from the consensus alone: if ATM/ATR phosphorylates menin directly, the site should be an S/T followed by Q. None of the four observed MEN1 phosphosites (S487, S543, S593, T594) is annotated as S/T-Q in the data this beat pulled, which means either the site is unobserved in public proteomics or the phosphorylation is indirect.
Why two opposite kinase inputs on menin matter for the fusion
Menin is the handle. Two kinase inputs move it in opposite directions:
| input | direction | system | entry |
|---|---|---|---|
| PKA (GLP-1) at S487 | off chromatin, sequestered by actin/myosin | beta cells | mechanism-pka-menin-s487-chromatin-release |
| ATM/ATR after DNA damage | stabilised, more menin | melanocytes | this entry |
Neither has been measured in a KMT2A-rearranged cell. If DNA-damaging chemotherapy - which every one of these patients receives - raises menin levels through ATM/ATR, then the size of the target a menin inhibitor is aimed at may be a function of the chemotherapy the patient is on. That is a pharmacodynamic interaction nobody in this literature has raised, and it is testable in existing cell lines with a western blot.
| kinase | ATM/ATR |
|---|---|
| substrate | gene-men1 |
| uniprot | O00255 |
| site | unmapped |
| consequence | increased MEN1 protein levels after DNA damage; transactivation of BRCA1, RAD51, RAD51AP1 |
| system | melanocytes and melanoma |
| tested in leukaemia | false |
| readability | primary paper PMID 23648481 abstract-only; fullTextXML HTTP 500 and efetch db=pmc body-less on 2026-09-19 |
- If chemotherapy raises menin levels, then menin inhibitor given after or with a DNA-damaging agent may face a larger target pool than the dose was set against. Sequence and timing would matter in a way no current protocol accounts for.
- ATR inhibitors are in paediatric development. Combining one with a menin inhibitor could lower menin levels through this axis while blocking the pocket through the drug - attractive on paper, and it is also two hits on the DNA damage response in a marrow already compromised by the leukaemia.
- The entire claim rests on one sentence of one abstract in a melanoma paper whose full text this session could not open. It is recorded as a lead with its unreadability stated, not as a mechanism to act on.
- Which residue? Nobody has mapped it, and an S/T-Q scan of O00255 would give a shortlist in minutes.
- Do the DNA-damaging agents in infant ALL and AML protocols raise menin protein in KMT2A-rearranged cells? If so, does that change menin-inhibitor pharmacodynamics when the two are given in sequence?
- Is the effect on menin abundance or on menin chromatin occupancy? The two have different consequences for a competitive inhibitor.
- Does ATM/ATR phosphorylate menin directly, or is the level change downstream of the damage response?
- E1moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper
Following DNA damage, MEN1 levels increase as a result of phosphorylation by the DNA damage kinase ATM/ATR, and menin stimulates transcription of BRCA1, RAD51 and RAD51AP1 with the mixed-lineage leukaemia histone methyltransferase as coactivator, recruited to those promoters by estrogen receptor 1 with increased H3K4 trimethylation.
MEN1 is a melanoma tumor suppressor that preserves genomic integrity by stimulating transcription of genes that promote homologous recombination-directed DNA repair. · Fang M, et al. · Mol Cell Biol 2013What this evidence cannot show
KNOWN BUT NOT FULLY READ - abstract only. Europe PMC fullTextXML returned HTTP 500 for PMC3700119 on 2026-09-19 and efetch db=pmc returned a well-formed record with no body element. The system is melanocytes and melanoma, not haematopoietic; no phosphorylation site is named in the abstract; 'phosphorylation by ATM/ATR' as stated does not distinguish a direct substrate relationship from a downstream consequence of DNA-damage signalling.
Evidence that argues against this (1)
- This paper's framing is that MEN1 is a tumour suppressor whose loss drives melanoma, the opposite of its role in KMT2A-rearranged leukaemia where menin is a required cofactor for the fusion. A regulatory input that raises menin levels is protective in the paper's system and would be expected to be harmful in the leukaemia, so the mechanism does not transfer with its sign intact. Huang J et al. 2012
- E2moderate confidence 3 of 5: One strong study, or several smaller consistent ones.database
Only four phosphorylation sites are observed on menin (O00255) in the PRIDE/PTMeXchange re-analysis - S487, S543, S593 and T594 - and none of them is attributed to ATM or ATR in any source this beat could read.
What this evidence cannot show
Fetched 2026-09-19. Four sites on a 610-residue protein is near the detection floor for a protein of menin's abundance, so an unobserved ATM/ATR site is entirely expected and this is weak evidence about the site's existence. DNA-damage-induced phosphorylation is by definition conditional and public shotgun runs are mostly unstimulated.
Evidence that argues against this (1)
- A conditional, stimulus-dependent phosphosite is precisely the class that pooled public re-analysis systematically misses, so an absence here is close to uninformative - the same limitation this beat applied to the S821 negative, and it must be applied symmetrically. Casado P et al. 2023
DNA damage raises menin levels via ATM/ATR phosphorylation; residue unmapped
- related to →PKA phosphorylates menin at Ser487 and pulls it off chromatin - a kinase input on the drug target itself
the opposite-direction kinase input on the same target
PMID 23648481: fullTextXML HTTP 500 and body-less efetch db=pmc
Adds PMID 16690369, previously uncited here: menin's chromatin pool rises 2.8-fold after UV and is ATR-CHK1 dependent
tested against this thread and found NOT to belong to it; recorded as a negative