RAD51 - the one repair protein measured AT the KMT2A translocation hotspot, and ATM controls how much of it loads there

{
  "site": "11q23 KMT2A translocation breakpoint hotspot",
  "perturbation": "ATM deficiency plus etoposide",
  "result": "excessive RAD51 binding; RPA and INO80 binding also increased",
  "authors_model": "ATM averts translocation by preventing excessive loading of recombination proteins at translocation hotspots",
  "pmid": "21048951",
  "note": "the only measurement of any repair protein AT the KMT2A hotspot found in this beat",
  "title": "ATM modulates the loading of recombination proteins onto a chromosomal translocation breakpoint hotspot.",
  "authors": "Sun J, Oma Y, Harata M, et al.",
  "venue": "PLoS One",
  "year": 2010,
  "title_provenance": "Title/authors/venue backfilled from PubMed esummary on 2026-09-20 because this citation stored a bare PMID with no title, which made it unscoreable by verify-citations.py. BACKFILLING IS NOT VERIFICATION: it confirms the PMID resolves to a real paper, not that this is the right paper for the claim. That still requires reading."
}

{
  "chronos_mean_kmt2a_rearranged": -1.2369,
  "chronos_mean_other_leukaemia": -1.2966,
  "difference": 0.0597,
  "pan_essentiality_all_lines": -1.2439,
  "selectivity_rank": 15440,
  "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."
}

{
  "CONSTITUTIVE": "NUCLEOPLASMIC AND CHROMATIN-ASSOCIATED, WITH REAL MINOR POOLS OUTSIDE THE NUCLEUS. UniProt Q06609 (fetched live 2026-09-21) carries SIX location values: 'Chromosome' on EIGHT ECO:0000269 attributions, 'Nucleus' on NINE, 'Cytoplasm' on two, 'Cytoplasm, perinuclear region' on one, 'MITOCHONDRION MATRIX' on one and 'Cytoplasm, cytoskeleton, microtubule organizing center, CENTROSOME' on one [E_q91_rad51_loc1]. The nuclear residence is actively maintained: the feature table annotates a NUCLEAR EXPORT SIGNAL at RESIDUES 245-260 described as MASKED BY THE INTERACTION WITH BRCA2, so RAD51's nuclear pool is held there by a partner rather than by an import signal alone.",
  "INDUCED_AND_IT_IS_THE_DOMINANT_FACT": "DNA damage induces an INCREASE IN NUCLEAR LEVELS of RAD51 and its accumulation into MULTIPLE NUCLEAR FOCI, colocalising with RAD51AP1 and RPA2; together with FIGNL1 it is redistributed into discrete damage-induced foci after ionising radiation or camptothecin; and its accumulation at damage sites requires SPIDR and the MCM9-MCM8 complex [E_q91_rad51_loc1]. Eight of the nine 'Nucleus' attributions and all eight 'Chromosome' attributions sit in this induced literature, so a resting-state answer for RAD51 is a statement about the smaller part of the record.",
  "THE_LOCUS_LEVEL_ANSWER_IS_THIS_GRAPHS_OWN": "In this disease the useful localisation of RAD51 is not a compartment but a genomic position: ATM deficiency results in EXCESSIVE BINDING OF RAD51 AT THE TRANSLOCATION BREAKPOINT HOTSPOT OF 11q23 after etoposide, with increased RPA and INO80 binding (this entry's E2, PMID 21048951). That is RAD51 localised to the exact lesion this project exists to explain."
}

{
  "for_the_hotspot_result": "The one measurement at the right place was made in an ATM-deficient background after etoposide (this entry's E2); the fusion-context control is human, from MLL-AF4 and AF4-MLL AAVS1 knock-ins showing UNCHANGED RAD51 LEVELS and identical homologous-recombination efficiency (this entry's E3, PMID 27119507).",
  "in_this_disease": "MLL-fusion leukaemia is DDR-proficient and PARP-inhibitor-insensitive, partly because HOXA9 activates HR-associated genes (this entry's E4) - so the cell-type statement about RAD51 here is that the KMT2A-rearranged blast is HR-COMPETENT, which is a negative for therapeutic exploitation and a positive for the breakage model.",
  "never_imaged_here": "RAD51 foci have never been counted in a KMT2A-rearranged blast of either lineage in anything this beat retrieved; RAD51[tiab] AND KMT2A[tiab] = 0 and RAD51[tiab] AND MLL[tiab] = 5 [E_q91_rad51_loc2]."
}

{
  "DAMAGE_STATE_IS_THE_STATE": "Undamaged and damaged cells have different RAD51 distributions AND different nuclear amounts - damage increases nuclear levels as well as redistributing the protein into foci [E_q91_rad51_loc1]. Both must be stated; a focus count alone confounds redistribution with import.",
  "BRCA2_STATE": "The 245-260 nuclear export signal is MASKED BY BRCA2 [E_q91_rad51_loc1], so RAD51's compartment is a function of BRCA2 availability. In a BRCA2-deficient or BRCA2-saturated cell RAD51 is more exportable, which is a mechanistic route from a partner's abundance to a localisation phenotype and has never been examined in leukaemia.",
  "CELL_CYCLE_AND_MITOCHONDRIAL": "Separate minor pools - centrosome/MTOC, where HR proteins are required for mitotic function, and the mitochondrial matrix, where RAD51 maintains the mitochondrial genome [E_q91_rad51_loc1]. Neither belongs in the nuclear story and both are in the same UniProt list."
}

{
  "date": "2026-09-22",
  "tool": "NCBI esearch db=pubmed",
  "run_by": "Q91",
  "queries": [
    {
      "query": "RAD51[tiab] AND nucleolar[tiab]",
      "querytranslation": "\"RAD51\"[Title/Abstract] AND \"nucleolar\"[Title/Abstract]",
      "count": 17,
      "on_topic_as_a_residence_claim": 0,
      "note": "not a residence literature; RAD51 at rDNA under damage is a different claim from a nucleolar pool, and this entry makes neither"
    },
    {
      "query": "RAD51[tiab] AND MLL[tiab]",
      "querytranslation": "\"RAD51\"[Title/Abstract] AND \"MLL\"[Title/Abstract]",
      "count": 5
    },
    {
      "query": "RAD51[tiab] AND KMT2A[tiab]",
      "querytranslation": "\"RAD51\"[Title/Abstract] AND \"KMT2A\"[Title/Abstract]",
      "count": 0
    }
  ],
  "reading": "The absence bounded is a CONSTITUTIVE subnuclear compartment and any imaging in a KMT2A-rearranged cell. The induced-foci literature is enormous and is not in question. Titles and abstracts only (rule 80). RAD51A, RECA and HsRAD51 were not run as separate operands.",
  "absence_class": "never-measured"
}