Oncofusion

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Genemoderate confidence 3 of 5: One strong study, or several smaller consistent ones.Q35-encode-reanalysis

MRE11 (P49959, 708 aa) - the nuclease that makes the first cut of end resection, named in 10 entries of this graph and never written; DepMap mean -0.542 with 56% of 1,258 lines below -0.5, the deepest dependency in the whole resection cascade

also called MRE11A · MRE11 homolog 1 · meiotic recombination 11 · hMre11 · MRN complex nuclease

MRE11 is the enzyme that makes the first nick when a cell starts chewing back a broken DNA end, which is the step that commits the break to being repaired by copying a sister chromosome. Almost every cancer cell line needs it.

The same thing, for a scientist

**Named in 10 entries and never written.** MRE11 is the nuclease subunit of the MRN complex (MRE11-RAD50-NBN) and, with CtIP/RBBP8, performs the endonucleolytic incision that initiates short-range resection - the step immediately upstream of the EXO1/DNA2 long-range resection this graph's CTCF/HP1-gamma cascade is proposed to license. **It is therefore the missing first link of a chain this graph already carries at both ends** (`gene-rbbp8` exists; `gene-exo1` and `gene-dna2` exist). **The dependency is the deepest in the cascade, and the MRN complex is not internally coherent.** One Open Targets call, one release: | gene | mean Chronos | % of lines below -0.5 | screens | |---|---:|---:|---:| | **MRE11** | **-0.542** | **56.1%** | 1,258 | | BRCA2 | -0.519 | 53.0% | 1,258 | | BRCA1 | -0.489 | 44.0% | 1,258 | | PALB2 | -0.339 | 23.9% | 1,258 | | **NBN** | **-0.047** | **1.3%** | 1,258 | **MRE11 and NBN are subunits of the same three-protein complex and differ by a factor of eleven on the mean.** That is a genuine finding of this pass and it is not explained here: it may reflect MRN-independent MRE11 function, it may reflect that NBN loss is tolerated because ATM signalling degrades gracefully, or it may be a screening artefact. It is recorded, not resolved. **In this disease: essentially nothing.** Run live 2026-09-22, one `[tiab]` tag per term, every `querytranslation` read back: `MRE11[tiab] AND MLL[tiab]` = **0** (non-empty translation, `warninglist.outputmessages = ['No items found.']`); `MRE11[tiab] AND KMT2A[tiab]` = **1**, PMID 40788108, which is about ATG4B nuclear translocation and PRMT1-mediated repair in leukaemia and is not a KMT2A-locus measurement. **So the nuclease that initiates the resection reaction this graph's central hypothesis is about has never been connected to KMT2A in a title or abstract.** **And it is not in ENCODE.** Like BARD1, EXO1 and DNA2, MRE11 has no released human TF ChIP-seq experiment, so the compute route that closed the BRCA1 and CBX3 questions does not exist for it. ChIP is in any case a poor instrument for a transient nuclease at a resected end; END-seq and ssDNA-resection qPCR are the right assays and neither has been run at this locus.

Facts and figures
gene symbolMRE11
uniprotP49959
uniprot entry nameMRE11_HUMAN
gene primary readbackMRE11
length AA708
protein nameDouble-strand break repair protein MRE11
how the accession was resolvedgene_exact:MRE11 AND organism_id:9606 AND reviewed:true returned exactly ONE reviewed record and its primary gene name reads back as MRE11 (rules 62/65). Accession and length are both asserted so verify-accessions.py can catch a swap.
domains noteUniProt P49959 declares NO Domain features, so data.domains is deliberately EMPTY rather than populated with invented boundaries. The nuclease and capping domains described in the structural literature are not in this record's feature table and were not looked up here.
localizationNucleus; Chromosome; Chromosome, telomere (UniProt P49959)
subnuclear localizationionising-radiation-induced foci at double-strand breaks; telomeres
localization shown for fusionNO - nobody has looked in any fusion, and no ENCODE ChIP-seq experiment for MRE11 exists in any cell type
shown for fusionNO - nobody has looked in any KMT2A fusion
cell typenot measured in any haematopoietic cell in the context of this locus
cell statedamage-conditional by construction - MRE11 acts at a break, so a resting-state measurement would be uninformative even if one existed
epigenetic readoutnone directly; MRE11 acts on DNA ends, not on histone marks, and its recruitment is downstream of the H3K9/HP1 chromatin state this graph's cascade describes
encode statusNO released human TF ChIP-seq experiment - the search endpoint returns no target record, as for BARD1, EXO1 and DNA2. The compute route that closed the BRCA1 and CBX3 questions is unavailable.
absence classnever-measured
relationship to existing entriesgene-rbbp8 (CtIP) exists and is MRE11's partner in the initiating incision; gene-exo1 and gene-dna2 exist and are the downstream long-range nucleases. This entry is the missing first step between them, and it is written because the chain in hyp-the-menin-arm-and-the-ctcf-arm-license-consecutive-steps-of-one-resection-reaction currently jumps from CtIP to EXO1/DNA2 without naming the nuclease that makes the cut.
gene synonyms in uniprot
[
  "HNGS1",
  "MRE11A"
]
domains
[]
depmap
{
  "source": "Open Targets Platform 26.06 (meta.dataVersion year 26 month 06), fetched 2026-09-22",
  "gene_effect_metric": "Chronos",
  "n_screens_this_gene": 1258,
  "mean_gene_effect": -0.5423,
  "n_lines_below_minus_0_5": 706,
  "fraction_below_minus_0_5": 0.5612,
  "min": -1.8033,
  "max": 0.2204,
  "approvedSymbol_readback": "MRE11",
  "release_note": "rule 83: no release id in the payload, so the Open Targets dataVersion is recorded. Screen count is gene-specific (1258).",
  "no_median_split": "rule 84: no anti-selective-half tally reported.",
  "live_low_screen_control": "OR4F5 (ENSG00000186092), same session: approvedSymbol reads back but only 3 tissue blocks / 5 screens are returned - a passing symbol readback is not evidence the payload is populated."
}
mrn complex internal asymmetry
{
  "MRE11_mean": -0.5423,
  "NBN_mean": -0.0471,
  "ratio": 11.5,
  "note": "same complex, same call, same release, eleven-fold apart on the mean. Unexplained here. RAD50 was not fetched."
}
bounded absence 2026 09 22
{
  "instrument": "PubMed esearch, one [tiab] tag per term, every querytranslation read back",
  "MRE11[tiab] AND MLL[tiab]": {
    "count": 0,
    "querytranslation": "\"MRE11\"[Title/Abstract] AND \"MLL\"[Title/Abstract]",
    "warninglist": "No items found."
  },
  "MRE11[tiab] AND KMT2A[tiab]": {
    "count": 1,
    "pmid": "40788108",
    "title_checked": "Energy Deficiency-Induced ATG4B Nuclear Translocation Inhibits PRMT1-Mediated DNA Repair and Promotes Leukemia Progression - off topic for a KMT2A-locus measurement",
    "on_topic": 0
  },
  "name_list_searched": [
    "MRE11"
  ],
  "names_NOT_searched": [
    "MRE11A (the retired official symbol)",
    "hMre11",
    "MRN",
    "the complex name as a phrase"
  ],
  "why_that_matters": "rule 64 - a counted absence on a complex SUBUNIT must be paired with the complex form, and 'MRN complex' was not run. Rule 40's retired-symbol lesson also applies: MRE11A is the symbol most of the older literature uses.",
  "absence_class": "never-measured"
}
Still open
  1. Why is MRE11 an eleven-fold deeper dependency than NBN when they are subunits of the same complex? RAD50 was not fetched and would discriminate between 'the nuclease matters and the scaffold does not' and 'NBN is the odd one out'.
  2. Has resection at the KMT2A breakpoint cluster ever been measured by END-seq, BLESS or ssDNA-resection qPCR, in any cell? The ChIP-shaped question is unanswerable for MRE11 and this is the assay that would work.
  3. Does the bounded absence survive the complex form and the retired symbol? MRE11A and 'MRN complex' were not searched, and rule 64 says a subunit absence is not bounded until the complex form is run.
Every source behind this entry (2)
  1. E1established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paper

    MRE11 is a 708-residue human nuclease with UniProt accession P49959, localised to the nucleus, chromosomes and telomeres, and biallelic hypomorphic mutation of it causes an ataxia-telangiectasia-like disorder - which establishes it as a non-redundant double-strand-break repair gene in humans.

    PMID 10612394DOI
    What this evidence cannot show

    The disease genetics establish that MRE11 function is required in humans; they say nothing about this locus, this disease or this fusion. The accession, length and localisation are from UniProt, not from that paper.

    Evidence that argues against this (1)
    • ATLD patients survive to adulthood, so MRE11 hypomorphism is tolerated at the organism level, which sits awkwardly beside a DepMap profile showing 56% of cultured lines below -0.5. Cultured-line fitness and organismal viability are different questions and the entry should not be read as saying MRE11 is undruggable on safety grounds. UniProt Consortium 2026
  2. E2strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.database

    MRE11 has a mean DepMap Chronos gene effect of -0.542 across 1,258 lines with 56.1% below -0.5, while NBN - a subunit of the same MRN complex, fetched in the same call against the same release - has a mean of -0.047 with 1.3% below -0.5.

    DepMap CRISPR gene-effect (Chronos) for MRE11, served by the Open Targets Platform GraphQL API · Broad Institute DepMap / Open Targets Platform · Open Targets Platform 26.06 (meta.dataVersion year 26 month 06), fetched 2026-09-22 2026
    What this evidence cannot show

    Rule 83: no release id is returned in the payload, so the Open Targets dataVersion 26.06 is recorded instead; screen counts are gene-specific. Rule 84: no median-split proportion is reported. A Chronos score is 21-day fitness in cultured cancer lines and is not a safety or tractability statement.

    Evidence that argues against this (1)
    • An eleven-fold difference between two subunits of one obligate complex is more often an instrument result than a biological one - differential guide efficiency, differential essentiality of a scaffolding versus a catalytic subunit, or partial redundancy in ATM signalling downstream of NBN would all produce it. The entry records the asymmetry and does not interpret it. Broad Institute DepMap / Open Targets Platform 2026
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