FANCG — FA core complex; rank 27 of 8,269 for KMT2A-selective dependency, and no KMT2A literature at all

{
  "depmap_common_essential": false,
  "chronos_mean": -0.0905,
  "frac_lines_below_minus_0_5": 0.046
}

{
  "chronos_mean_kmt2a_rearranged": -0.463,
  "chronos_mean_other_leukaemia": -0.1463,
  "difference": -0.3168,
  "pan_essentiality_all_lines": -0.0905,
  "selectivity_rank": 75,
  "rank_denominator": 17728,
  "provenance": "Joined 2026-09-21 from analyses/depmap-kmt2a-selective-scan-full (generated 2026-09-19T10:12:06Z), the project's own genome-wide scan over 11 KMT2A-rearranged and 43 other leukaemia DepMap lines. NOT re-fetched and NOT independent of that scan: every caveat it carries applies here, including that the KMT2A-rearranged arm is a small number of lines drawn from nine individuals, that the rank denominator is 17,728 genes, and that a difference is not a dependency. Added because only 26 of 308 gene entries carried this number, which made any KMT2A-selectivity question answerable for 8% of the corpus.",
  "how_to_read": "A negative difference means MORE required in KMT2A-rearranged lines than in other leukaemia lines. A rank near 17,728 is ANTI-selective. Neither is evidence of a fusion-driven dependency on its own: check pan_essentiality_all_lines before calling anything selective, and note that a paralogue-redundant gene can score near zero for reasons that have nothing to do with this disease - see ana-the-paralogue-redundancy-excuse-is-not-tested-and-my-proxy-decided-the-answer."
}

{
  "kmt2a_records_raw": 5,
  "kmt2a_records_title_checked": 1,
  "leukaemia_records": 33,
  "aliases_searched": [
    "FANCG",
    "XRCC9"
  ],
  "kmt2a_query": "(KMT2A[tiab] OR MLL[tiab] OR \"mixed-lineage leukemia\"[tiab]) AND (FANCF[tiab] OR FANCA[tiab] OR FAA[tiab] OR FACA[tiab] OR FANCH[tiab] OR FANCG[tiab] OR XRCC9[tiab])",
  "leukaemia_query": "(FANCG[tiab] OR XRCC9[tiab]) AND (leukemia[tiab] OR leukaemia[tiab])"
}

{
  "subcellular": "NUCLEUS AND CYTOPLASM, WITH THE NUCLEAR FORM MAJOR - AND THE ONLY CODED CITATION IS NOT A LOCALISATION STUDY. UniProt O15287 fetched 2026-09-21 annotates 'Nucleus' and 'Cytoplasm', both at ECO:0000269 and both citing the SAME single reference, PubMed:18550849, which is a paper identifying HES1 as an interactor of the FA core complex [E_q77_loc2]. The partition statement - 'The major form is nuclear. The minor form is cytoplasmic' - is carried in an UNCODED note [E_q77_loc1]. The founding observations that FANCG is a component of a NUCLEAR complex with FANCA and FANCC, and that FANCG drives the complex's nuclear accumulation, are in two 1999-2000 papers that the record does not cite [E_q77_loc3].",
  "subnuclear": "NOT MEASURED FOR FANCG ITSELF, AND THE FA PATHWAY'S SUBNUCLEAR CURRENCY BELONGS TO A DIFFERENT PROTEIN. The canonical subnuclear readout of this pathway is monoubiquitinated FANCD2/FANCI assembling into nuclear FOCI at damage sites; FANCG's job is upstream of that, as part of the core complex that installs the mark. No focus, body, matrix or chromatin-fraction measurement of FANCG was found in this beat. What IS established, and is a subnuclear-adjacent mechanism rather than an address, is that FANCG CONTROLS ANOTHER SUBUNIT'S NUCLEAR ACCUMULATION: FANCG binds directly to the amino-terminal NUCLEAR LOCALIZATION SEQUENCE of FANCA, and correcting an FA-G cell line restores FANCA/FANCG binding, prolongs FANCA's half-life and INCREASES NUCLEAR ACCUMULATION of the FA protein complex [E_q77_loc3]. So for FANCG the interesting spatial fact is not where it is but what it moves.",
  "how_shown": "co-immunoprecipitation and complex characterisation for the HES1 interaction [E_q77_loc2]; complementation of FA-G and FA-A cell lines with half-life and nuclear-accumulation readouts, plus binding mapping to FANCA's N-terminal NLS [E_q77_loc3]",
  "systems": "human FA patient-derived and corrected lymphoblast and fibroblast lines. Haematopoietic in origin for some of the FA lines, which is better than most of this tranche - but NOT leukaemic, NOT fusion-bearing and NOT a primary blast.",
  "shown_for_fusion_localisation": "NO - nobody has looked in any fusion. This entry already records that there is NO published literature on FANCG in KMT2A-rearranged leukaemia at all - 5 records raw, 1 substantive after title-checking, and zero for FANCG or XRCC9 alone against KMT2A or MLL. A localisation measurement in a fusion context is therefore absent for the same reason everything else is: nobody has studied this gene in this disease, despite its rank of 75 of 17,728 in the project's own selectivity scan.",
  "node": "localization-chromatin-bound-versus-soluble-fraction-kmt2a",
  "the_rule_91_case_here_is_a_replaceable_citation": "Unlike the MED26 or STAG2 cases in this tranche, where the experimental record is simply absent from the database, FANCG's problem is a REPLACEABLE POINTER. UniProt's sole experimental citation for both of FANCG's compartments is a 2008 HES1 interaction paper, while two papers from 1999 and 2000 establish that FANCG is a component of a functional NUCLEAR complex and that it promotes the complex's nuclear accumulation by binding FANCA's NLS. Brief rule 91 item 3 asks that the founding observation be named when it differs from the database's, and this entry names it."
}

{
  "evidence_class_key": "concept-expressed-required-maintains-three-evidence-classes",
  "identifier_note": "FANCG is O15287, 622 aa, synonym XRCC9. data/symbol-collisions.json was grepped for FANCG and XRCC9 before the first query and has NO row for either; none is proposed. This entry's existing literature block already records that the alias XRCC9 was searched, which is the relevant discipline for a gene whose 1990s literature is indexed under the old symbol.",
  "expressed_in": {
    "class": 1,
    "summary": "ubiquitous; not pan-essential (mean Chronos -0.0905, 4.6% of lines below -0.5, per this entry's own [E4]). The cell type that matters for FA biology is the haematopoietic stem and progenitor compartment, and it matters because of what happens when the pathway is lost, not because of where the gene is expressed."
  },
  "required_in": {
    "class": 2,
    "claim": "IN HUMANS, LOSS OF THE FANCONI ANAEMIA PATHWAY - OF WHICH FANCG IS A CORE-COMPLEX SUBUNIT - PRODUCES A PROFOUND HAEMATOPOIETIC STEM AND PROGENITOR CELL DEFECT THAT IS PRESENT BEFORE CLINICAL MARROW FAILURE. In FA patients, HSPCs are profoundly depleted before the onset of clinical bone-marrow failure; in response to replicative stress and unresolved DNA damage, p53 is HYPERACTIVATED in FA cells and triggers a late p21-dependent G0/G1 CELL-CYCLE ARREST; and knocking down p53 RESCUES the HSPC defect in several in vitro and in vivo models including human FA and FA-like cells [E_q77_ct1].",
    "pmids": [
      "22683204"
    ],
    "system_named_in_the_claim": "HUMAN Fanconi anaemia patient haematopoietic stem and progenitor cells, plus in vitro and in vivo FA-like models - human primary material, no fusion",
    "nodes": [
      "cell-type-hsc-bone-marrow"
    ],
    "the_pathway_versus_the_subunit": "Brief rule 64 in the direction that usually gets forgotten: this is a PATHWAY result, not a FANCG result. The cohort is Fanconi anaemia patients across complementation groups, and nothing here isolates FANCG. It is recorded as the cell-type answer for this entry because the core complex is obligate - FANCG is required for FANCA and FANCC to bind at all - and because there is no FANCG-specific haematopoietic experiment in existence."
  },
  "context": "human FA patients and FA-like models; no fusion and no leukaemia in the cited work"
}

{
  "evidence_class_key": "concept-expressed-required-maintains-three-evidence-classes",
  "maintains_state": {
    "class": 3,
    "states": [
      "cell-state-replication-stress-icl-repair",
      "cell-state-quiescence"
    ],
    "claim": "LOSING THE FA PATHWAY DOES NOT KILL A PROGENITOR - IT ARRESTS IT, AND THE ARREST IS p53/p21-DEPENDENT AND REVERSIBLE. In human FA cells, replicative stress and unresolved DNA damage hyperactivate p53, which triggers a LATE p21-dependent G0/G1 arrest; p53 knockdown rescues the HSPC defect [E_q77_ct1]. So the state is an exacerbated but physiological damage response rather than a repair catastrophe, and the arrest is the pathogenic event.",
    "pmids": [
      "22683204"
    ],
    "system_named_in_the_claim": "human FA patient HSPCs and FA-like in vitro and in vivo models - no fusion"
  },
  "why_this_bears_on_the_scan_hit": "This entry exists because FANCG ranks 75 of 17,728 for KMT2A-selective dependency in the project's own scan. A CRISPR proliferation screen scores a p53/p21-dependent G0/G1 arrest as depletion, indistinguishably from killing - and FA pathway loss produces exactly that arrest. So the mechanism behind the scan signal may be an arrest rather than a vulnerability, which matters therapeutically: a drug that arrests blasts through p53 is a different proposition from one that kills them, and KMT2A-rearranged lines' p53 status varies. This graph's TP53 entry records that TP53 is effectively absent at diagnosis in infants and enriched at relapse, which predicts that any FA-pathway-directed effect would WEAKEN in relapsed disease. That prediction is testable in existing DepMap data by splitting lines on TP53 status and has not been run.",
  "confidence": "moderate",
  "caveats": "The cell-type and cell-state evidence is PATHWAY-level across Fanconi anaemia complementation groups, not FANCG-specific, and this entry's own analysis already notes that the obligate FA core subunits do NOT move together in the DepMap data - which is hard to reconcile with a canonical pathway dependency and equally hard to reconcile with treating a pathway result as a subunit result. No fusion anywhere. And this entry's [E7] is the standing objection to the whole line: Fanconi anaemia patients, who have no FA pathway at all, nonetheless develop KMT2A-rearranged leukaemia.",
  "counter_evidence": [
    {
      "note": "The decisive counter-argument to any FA-pathway requirement in this disease is already in this entry at [E7] and it is a human observation, not a model: Fanconi anaemia patients are biallelically null for an FA gene and still develop KMT2A-rearranged leukaemia - a documented therapy-related AML carrying MLL-CBP t(11;16) in a child with FA. If the pathway were required for KMT2A-rearranged leukaemogenesis, that case could not exist. The DepMap signal must therefore be about maintenance of established lines rather than about initiation, and the two are routinely conflated.",
      "citation": {
        "title": "Fanconi anemia proteins FANCA, FANCC, and FANCG/XRCC9 interact in a functional nuclear complex.",
        "authors": "Garcia-Higuera I, Kuang Y, Näf D, Wasik J, D'Andrea AD",
        "year": 1999,
        "venue": "Mol Cell Biol",
        "pmid": "10373536",
        "doi": "10.1128/MCB.19.7.4866",
        "type": "paper"
      }
    }
  ]
}