MEN1 (menin, human, UniProt O00255) - curation notes

Deep research status: automated deep research (falcon / Edison) FAILED with an
authentication error on 2026-10-24, and no other provider key was usable. No
-deep-research-*.md file exists for this gene. The notes below come from my own
reading of the cached publications in publications/, the UniProt record
(MEN1-uniprot.txt), cached Reactome entries, and QuickGO queries (2026-10-24).

Why this gene was reviewed

Rule FRR:0009 (projects/FUNCTION_REQUIREMENT_RULES.md) flagged menin's
"DNA-binding transcription activator activity" (GO:0001216) annotation: human GOA has
it as IEA (GO_REF:0000107, Ensembl Compara transfer from mouse O88559). Menin has no
recognized sequence-specific DNA-binding domain.

Tracing the IEA (QuickGO, 2026-10-24)

• Human row: GO:0001216 IEA GO_REF:0000107, WITH UniProtKB:O88559 / ensembl:ENSMUSP00000058149.
• Source on mouse menin O88559: GO:0001216 IDA PMID:14992727, assigned_by UniProt.
  PMID:14992727 (Hughes et al. 2004) shows menin co-purifies with an MLL2/Ash2L H3K4
  methyltransferase complex, binds Ser5-phosphorylated Pol II, is ChIP-bound at Hoxc8, and
  Men1-null cells lose Hoxc6/Hoxc8 expression ["Chromatin immunoprecipitation experiments
  reveal that menin is bound to the Hoxc8 locus."; "menin activates the transcription of
  differentiation-regulating genes by covalent histone modification"]. Nothing in it shows
  sequence-specific DNA binding by menin. The activity it supports is a coactivator /
  scaffold activity, not a DNA-binding TF activity -> source defect on the UniProt mouse
  row (GO:0001216 -> GO:0003713 transcription coactivator activity).
• Other mouse-sourced IEAs examined at the same time:
• GO:0043565 sequence-specific DNA binding <- mouse IDA PMID:20956546 (MGI). Onodera et
  al. 2010 is a ChIP study: "TrxG complex associated with the TrxG component Menin binds
  to the whole GATA3 gene locus". Locus occupancy by a complex is not sequence-specific
  DNA binding -> source defect (MGI).
• GO:0140608 cysteine-type endopeptidase activator activity <- mouse IDA PMID:14688275
  (MGI). Schnepp et al. 2004: "loss of menin reduces the expression of procaspase 8";
  menin raises caspase-8 levels (expression), it does not bind and activate the protease
  -> source defect (MGI).
• GO:0003677 DNA binding <- mouse IDA PMID:14992727 and PMID:24824656 (MGI). Human has a
  direct IDA for dsDNA binding (PMID:15331604), so the generic term is true.
• GO:0000781 chromosome, telomeric region <- mouse IDA PMID:12203793 (BHF-UCL): meiotic
  telomere localization only [PMID:12203793 "found that it localizes exclusively at
  telomeres"; "menin does not specifically associate with telomeres in somatic cells"].

DNA binding: non-specific, not TF-like

• La et al. 2004 PMID:15331604; binds Y-form, branched and 4-way junction DNA
  ["It also binds a variety of DNA structures, including Y-structures, branched structures,
  and 4-way junction structures."]; binding needs positively charged residues of NLS1/NLS2
  in the C-terminus; random-sequence probes bind and poly dI/dC competes ["menin not only
  binds to DNA in a non-sequence specific fashion"]. Disease truncations (R527X, M558X)
  lose DNA binding and fail to repress proliferation.
• Milne et al. 2005 PMID:15640349
• Locus targeting is through partners: MLL1-LEDGF (chromatin anchoring), JunD, c-Myb/GATA-3,
  SMAD3, NF-kB.

Core biology

1. Scaffold/adaptor of MLL1/MLL2 (KMT2A/KMT2B) H3K4 methyltransferase complexes.
   PMID:14992727; PMID:15199122;
   PMID:17500065. Crystal structures:
   PMID:22327296. MLL fusion oncoproteins need menin
   PMID:16239140. This
   dependency is the basis of menin-MLL inhibitors (PMID:22936661, MI-2/MI-2-2).
2. Coactivator of target genes (Hox genes, CDKN1B/p27, CDKN2C/p18, GATA3):
   PMID:15640349;
   PMID:15199122;
   PMID:20484083.
3. Corepressor of JunD (AP-1) and NF-kB: PMID:9989505; the same pocket binds JunD and MLL1 PMID:22327296; PMID:11526476; hTERT repression
   PMID:12837246;
   PMID:23784080.
4. Location: nucleus PMID:9465067,
   chromatin and nuclear matrix PMID:12874027. Minor cytoplasmic pools (cleavage furrow
   with NMHC II-A, PMID:14508515; Pem, PMID:11500056).

Peripheral / context-dependent

• TGF-beta/SMAD3 signaling (PMID:11274402), osteoblast differentiation via JunD
  (PMID:15563473), Th2 differentiation via GATA3 (PMID:20484083).
• DNA damage: FANCD2 association (PMID:12874027), relocation to chromatin after UV via
  ATR-CHK1 (PMID:16690369), S-phase checkpoint with CHES1/FOXN3 (PMID:16951149). No
  evidence that menin carries out a DNA repair step.
• JNK: Gallo et al. show menin does not affect JNK/ERK activation but blocks
  phosphorylation of Jun/Elk-1 targets PMID:12226747, so
  "negative regulation of JNK cascade" overstates.
• Reactome places menin in ER lumen only through the generic FAM20C-substrate reaction
  (R-HSA-8952289); menin is a nuclear protein, so that row was removed.

Review decisions (summary)

• GO:0001216 IEA -> MODIFY to GO:0003713 transcription coactivator activity, plus source
  defect on mouse O88559 UniProt IDA row.
• GO:0043565 IEA -> REMOVE (+ MGI source defect); GO:0140608 IEA -> REMOVE (+ MGI source defect).
• GO:0000976 rows (IBA, IDA, IEA) -> MARK_AS_OVER_ANNOTATED: ChIP occupancy reflects
  recruitment by DNA-binding partners, not sequence-specific binding by menin.
• Protein binding: JunD and NF-kB rows -> MODIFY to transcription corepressor activity;
  c-Myb/GATA-3 rows -> MODIFY to transcription coactivator activity; MLL1 row from the
  structure paper -> MODIFY to protein-macromolecule adaptor activity; other rows REMOVE as
  uninformative.