{"gene":"ATM","run_date":"2026-06-09T22:02:44","timeline":{"discoveries":[{"year":2003,"finding":"ATM is held inactive in unirradiated cells as a dimer or higher-order multimer, with the kinase domain bound to a region surrounding serine 1981 in the FAT domain. DNA damage induces rapid intermolecular autophosphorylation of serine 1981, causing dimer dissociation and initiating ATM kinase activity. ATM activation does not require direct binding to DNA strand breaks but may result from changes in chromatin structure.","method":"Phosphospecific antibody detection, immunoprecipitation, kinase activity assays, irradiation with defined doses","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods (phosphospecific antibody, Co-IP, in vitro kinase assay, site-directed mutagenesis of S1981), widely replicated finding","pmids":["12556884"],"is_preprint":false},{"year":2010,"finding":"ATM can be directly activated by oxidative stress in the absence of DNA double-strand breaks and the MRN complex. Oxidized ATM forms a disulfide-cross-linked dimer distinct from the inactive dimer seen in unirradiated cells. Mutation of a critical cysteine residue involved in disulfide bond formation specifically blocked activation through the oxidation pathway.","method":"In vitro kinase assay, non-reducing gel electrophoresis, cysteine mutagenesis, cell-based activation assays","journal":"Science","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstitution in vitro, mutagenesis of critical cysteine, multiple orthogonal methods in single rigorous study","pmids":["20966255"],"is_preprint":false},{"year":2005,"finding":"ATM and the nuclease activity of Mre11 are required for processing DNA double-strand breaks to generate RPA-coated ssDNA needed for ATR recruitment and subsequent Chk1 phosphorylation. ATM-dependent ATR activation in response to DSBs is restricted to S and G2 cell cycle phases and requires CDK kinase activity.","method":"Epistasis analysis with ATM inhibitor and Mre11 nuclease mutants, ChIP, immunofluorescence, flow cytometry, Chk1 phosphorylation assay","journal":"Nature Cell Biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis combined with biochemical readouts, pathway ordering demonstrated with multiple complementary approaches","pmids":["16327781"],"is_preprint":false},{"year":1996,"finding":"In S. cerevisiae, the ATM homolog TEL1 and the ATR homolog MEC1 have overlapping functions in response to DNA damage and replication blocks. Both MEC1 and TEL1 control phosphorylation of Rad53p (the RAD53/SAD1 checkpoint kinase) in response to DNA damage, placing RAD53 as a signal transducer downstream of these two kinases.","method":"Genetic suppressor screen, phosphorylation assays, overexpression studies in yeast","journal":"Science","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis with suppressor screen plus direct phosphorylation readout, foundational pathway-ordering result replicated by many subsequent studies","pmids":["8553072"],"is_preprint":false},{"year":2001,"finding":"In S. cerevisiae, Tel1 (ATM homolog) and the Mre11 complex define a DNA damage checkpoint pathway. The Tel1-Mre11 complex pathway activates Rad53 and its interaction with Rad9 in mitotic cells, while in meiosis it acts via Rad9 and Mek1. Activation depends on the Mre11 complex as a damage sensor and on unprocessed DSBs.","method":"Genetic epistasis, Rad53 phosphorylation assays, co-immunoprecipitation, meiotic and mitotic checkpoint analysis in yeast","journal":"Molecular Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis with multiple checkpoint readouts, reciprocal interaction studies, consistent with mammalian ATM/MRN pathway","pmids":["11430828"],"is_preprint":false},{"year":1999,"finding":"ATM kinase activity is directly inhibited by caffeine in vitro, and caffeine inhibits radiation-induced activation of Cds1/Chk2 in vivo. This provides a molecular explanation for caffeine's ability to override DNA-damage checkpoint responses.","method":"In vitro ATM kinase assay with caffeine, in vivo Cds1 phosphorylation assay","journal":"Current Biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct in vitro kinase assay plus in vivo corroboration, single lab but two orthogonal methods","pmids":["10531013"],"is_preprint":false},{"year":2003,"finding":"In budding yeast, Tel1 (ATM homolog) associates with DNA double-strand breaks through a mechanism dependent on the C terminus of Xrs2 (Nbs1 homolog). This association is required for activation of DNA damage responses including cell survival and Rad53 phosphorylation.","method":"ChIP of Tel1 at DSBs, C-terminal truncation of Xrs2, Rad53 phosphorylation assays","journal":"Genes & Development","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP demonstrating direct DSB association, genetic dissection of Xrs2 C-terminus requirement, functional readouts","pmids":["12923051"],"is_preprint":false},{"year":1999,"finding":"ATM is specifically cleaved and inactivated during apoptosis in a caspase-dependent manner. ATM is an efficient substrate for caspase-3 but not caspase-6 in vitro. Apoptotic cleavage of ATM abrogates its protein kinase activity against p53 but has no apparent effect on DNA binding properties of ATM.","method":"In vitro caspase cleavage assays, in vivo apoptosis induction with multiple stimuli, ATM kinase assay, DNA-binding assay","journal":"Molecular and Cellular Biology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro reconstitution with purified caspase-3, in vivo corroboration, multiple apoptotic stimuli tested, kinase and DNA-binding assays performed","pmids":["10454555"],"is_preprint":false},{"year":2008,"finding":"FOXO3a interacts with ATM to promote phosphorylation of ATM at Ser1981 and downstream mediator nuclear foci formation in response to DNA damage. The C-terminal domain of FOXO3a binds to the FAT domain of ATM. Silencing FOXO3a abrogates ATM-pS1981 and phospho-H2AX foci after DNA damage; increasing FOXO3a promotes ATM-regulated signaling and DNA repair.","method":"Co-immunoprecipitation, FOXO3a knockdown/overexpression, immunofluorescence for ATM-pS1981 and γH2AX foci, cell cycle checkpoint assays","journal":"Nature Cell Biology","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — reciprocal Co-IP plus functional knockdown/overexpression with multiple readouts, single lab","pmids":["18344987"],"is_preprint":false},{"year":2019,"finding":"ATM phosphorylates NCOA4, facilitating NCOA4-ferritin interaction and sustaining ferritinophagy (selective autophagic degradation of ferritin). This phosphorylation by ATM dominates intracellular labile free iron availability and is required for ferroptosis execution. ATM ablation-induced ferroptotic resistance is largely independent of TRP53.","method":"Pharmacological ATM inhibition, genetic ATM/Trp53 knockout (CRISPR), ferritinophagy assays, iron measurement, phosphorylation assays for NCOA4","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — genetic knockout combined with biochemical phosphorylation assay and ferritinophagy readout, single lab","pmids":["36752571"],"is_preprint":false},{"year":2019,"finding":"UFL1 (ufmylation E3 ligase) is recruited to DSBs by the MRE11/RAD50/NBS1 complex and monoufmylates histone H4 following DNA damage. Monoufmylated histone H4 promotes Suv39h1 and Tip60 recruitment to enable ATM activation. ATM phosphorylates UFL1 at serine 462, enhancing UFL1 E3 ligase activity and forming a positive feedback loop for ATM activation.","method":"Co-immunoprecipitation, ChIP, in vitro ufmylation assay, ATM kinase assay, knockdown experiments","journal":"Nature Communications","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — multiple biochemical assays including in vitro reconstitution steps, single lab, Co-IP and ChIP","pmids":["30886146"],"is_preprint":false},{"year":2019,"finding":"MRE11 is UFMylated on K282, and this modification is required for MRN complex formation under unperturbed conditions and for DSB-induced optimal ATM activation. A cancer-associated mutation MRE11(G285C) phenocopies the UFMylation-defective mutant MRE11(K282R), impairing ATM activation.","method":"Site-directed mutagenesis, Co-immunoprecipitation, ATM activation assays (pS1981), homologous recombination assays","journal":"Nucleic Acids Research","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — mutagenesis of specific lysine combined with functional ATM activation readout and Co-IP, single lab","pmids":["30783677"],"is_preprint":false},{"year":2011,"finding":"RNF8 and Chfr E3 ubiquitin ligases synergistically regulate histone ubiquitination to control histone H4 Lys16 acetylation through MRG15-dependent acetyltransferase complexes, thereby controlling chromatin relaxation and ATM activation following DNA damage. Loss of both RNF8 and Chfr suppresses DNA damage-induced ATM kinase activation.","method":"Double-knockout mouse model, immunofluorescence, kinase activity assays, histone modification analysis, in vivo tumor development","journal":"Nature Structural & Molecular Biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic double-knockout with biochemical readouts, in vivo mouse model, single lab","pmids":["21706008"],"is_preprint":false},{"year":2016,"finding":"Cryo-EM structure of intact homodimeric ATM/Tel1 from S. pombe reveals that two monomers contact head-to-head through FAT and kinase domains. The N-terminal helical solenoid tightly packs against FAT and kinase domains. The dimer interface and consecutive HEAT repeats inhibit binding of kinase substrates and regulators by steric hindrance.","method":"Cryo-EM single-particle reconstruction of full-length ATM/Tel1","journal":"Nature Communications","confidence":"High","confidence_rationale":"Tier 1 / Moderate — cryo-EM structure of intact complex providing direct structural evidence for inhibition mechanism, single lab but high-resolution method","pmids":["27229179"],"is_preprint":false},{"year":2016,"finding":"Single-particle electron microscopy of human dimeric ATM reveals that in the dimeric resting state, the active sites are buried, restricting substrate access. The N-terminal and C-terminal regions of ATM were localized by fitting of mTOR crystal structure into the EM map.","method":"Single-particle electron microscopy, structural fitting with mTOR crystal structure","journal":"Cell Cycle","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — EM structural data from single lab, resolution limited; structural conclusions consistent with other ATM structural studies","pmids":["27097373"],"is_preprint":false},{"year":2019,"finding":"Cryo-EM structure of nucleotide-bound Tel1 (ATM ortholog) reveals that catalytic residues are in a productive conformation for catalysis, but the PIKK regulatory domain insert restricts peptide substrate access and the N-lobe is in an open conformation, explaining the requirement for Tel1 activation. Structural comparisons suggest a conserved allosteric activation mechanism among PIKKs.","method":"Cryo-EM structure determination of nucleotide-bound Tel1","journal":"Structure","confidence":"High","confidence_rationale":"Tier 1 / Moderate — high-resolution cryo-EM with nucleotide bound providing mechanistic insight into substrate access restriction, single lab but rigorous structural method","pmids":["31740029"],"is_preprint":false},{"year":2009,"finding":"In S. cerevisiae, telomeric proteins Rif1 and Rif2 attenuate Tel1 recruitment to DNA ends through distinct mechanisms. Rif2 competes with Tel1 for binding to the C terminus of Xrs2, thereby preventing Tel1 localization to DNA ends. Once Tel1 is delocalized, MRX does not associate efficiently with Rap1-covered DNA ends.","method":"ChIP at telomeres, yeast two-hybrid, genetic epistasis, Rif2/Xrs2 binding competition assays","journal":"Molecular Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP demonstrating Tel1 localization changes, direct competition binding assay showing Rif2 and Tel1 compete for Xrs2 C-terminus, multiple complementary methods","pmids":["19217405"],"is_preprint":false},{"year":2008,"finding":"S. cerevisiae Tel2 interacts with Tel1 and is specifically required for Tel1 localization to a DNA break and its activation of downstream targets, even when Tel1 protein levels are high. Computational analysis revealed structural homology between Tel2 and Ddc2 (ATRIP), suggesting a common structural principle for partners of PI3K-like kinases.","method":"Co-immunoprecipitation, ChIP at DSBs, genetic analysis, computational structural analysis","journal":"Genes & Development","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP plus ChIP demonstrating localization requirement, functional readout of downstream targets, single lab","pmids":["18334620"],"is_preprint":false},{"year":2012,"finding":"Tel1 (ATM ortholog) and Rad3 (ATR ortholog) in fission yeast phosphorylate the telomere protein Ccq1 at Thr93. This phosphorylation is required for telomerase recruitment to telomeres; a ccq1-T93A mutant fails to recruit telomerase and shows gradual telomere shortening.","method":"In vitro kinase assay with purified Tel1/Rad3, phosphosite mutagenesis (T93A), telomerase ChIP, telomere length analysis","journal":"Genes & Development","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro kinase assay demonstrating direct phosphorylation, mutagenesis showing phosphosite is essential for telomerase recruitment, two orthogonal readouts","pmids":["22302936"],"is_preprint":false},{"year":2015,"finding":"Tel1 (ATM) in S. cerevisiae mediates distance-dependent DSB interference in cis during meiosis, in which the occurrence of a DSB suppresses adjacent DSB formation. Loss of Tel1 causes DSBs to cluster within discrete zones, and Tel1 kinase activity is required for this suppression.","method":"Spo11-oligonucleotide mapping, kinase-dead tel1 mutation analysis, genetic epistasis in yeast meiosis","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — kinase-dead mutation distinguishes kinase-dependent effects, genome-wide Spo11-oligonucleotide mapping providing mechanistic insight, two orthogonal approaches","pmids":["25539084"],"is_preprint":false},{"year":2009,"finding":"ATM phosphorylates RASSF1A on Ser131 in response to DNA damage, leading to activation of MST2 and LATS1 kinases and stabilization of p73. Polymorphism S131F in RASSF1A (at the ATM phosphorylation site) confers resistance to DNA-damaging agents.","method":"In vivo phosphorylation assay, site-directed mutagenesis of Ser131, kinase activity assays for MST2/LATS1, p73 stabilization assay","journal":"Current Biology","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — mutagenesis of ATM phosphosite with functional pathway readout, single lab","pmids":["19962312"],"is_preprint":false},{"year":2012,"finding":"NBS1 and ATMIN compete for ATM binding, controlling ATM signaling pathway choice. ATMIN is required for ATM signaling induced by chromatin stress but not DSBs (where NBS1 is required). Loss of one cofactor increases flux through the alternative pathway; NBS1/ATMIN double deficiency causes complete abrogation of ATM signaling.","method":"Co-immunoprecipitation, genetic deletion (atmin and nbs1 mutant cells), ATM substrate phosphorylation assays, radiosensitivity assays","journal":"Cell Reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP demonstrating competition, genetic double-knockout showing complete ATM pathway abrogation, multiple functional readouts","pmids":["23219553"],"is_preprint":false},{"year":2019,"finding":"Tel1 (ATM ortholog) activation requires Rad50 ATPase activity and long nucleosome-free DNA, but does not require DNA double-strand termini. Either Mre11 or Xrs2, but not both, is required in addition to DNA and Rad50. All three MRX subunits show physical association with Tel1.","method":"In vitro Tel1 kinase reconstitution with purified components, ATPase-dead Rad50 mutants, varying DNA substrates, physical binding assays","journal":"Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — biochemical reconstitution with purified components, systematic dissection of requirements using mutants and varied substrates, single lab","pmids":["31073030"],"is_preprint":false},{"year":2019,"finding":"The ATP-bound conformation of the Mre11-Rad50 (MR) complex is essential for Tel1/ATM activation. Separation-of-function alleles mre11-S499P and rad50-A78T specifically impair Tel1 activation by reducing Tel1-MRX interaction without impairing DSB repair. Molecular dynamics simulations show MR bound to ATP adopts a tightly closed conformation critical for Tel1 activation.","method":"Separation-of-function mutant analysis, ChIP for Tel1 at DSBs, Tel1 kinase assays, molecular dynamics simulations, Co-immunoprecipitation","journal":"Nucleic Acids Research","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — separation-of-function mutations with direct Tel1 activation readout, ChIP, Co-IP, and computational structural analysis, multiple orthogonal methods","pmids":["30698745"],"is_preprint":false},{"year":2011,"finding":"In S. cerevisiae, Tel1 promotes MRX retention at DSBs, which is important for end-tethering and DSB repair by both homologous recombination and NHEJ. Rif2, recruited to DSBs, counteracts Tel1's role in MRX accumulation and enhances ATP hydrolysis by MRX, attenuating MRX end-tethering function.","method":"ChIP, synthetic phenotype screen, DSB repair assays (HR and NHEJ), end-tethering assays, genetic epistasis","journal":"PLoS Biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and functional repair assays, genetic epistasis, single lab","pmids":["26901759"],"is_preprint":false},{"year":2011,"finding":"Tel1 (ATM) promotes nucleolytic processing (resection) of telomeres by promoting MRX activity. The hyperactive Tel1-hy909 variant shows increased association at DSBs with telomeric repeats and increases persistence of MRX and Est1 at DSBs adjacent to telomeric repeats, accounting for increased telomere resection and elongation. Rif2 cannot inhibit processing at Tel1-hy909 telomeres.","method":"ChIP, telomere resection assays, telomere length analysis, gain-of-function tel1-hy909 mutant","journal":"Molecular and Cellular Biology","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — ChIP and telomere functional assays, hyperactive mutant analysis, single lab","pmids":["22354991"],"is_preprint":false},{"year":2013,"finding":"In S. cerevisiae, Mec1 (ATR ortholog) regulates resection of DSB ends, and loss of Mec1 accelerates resection by reducing Rad9 loading at DSBs. Extensive resection caused by Mec1 loss leads to prolonged MRX presence at DSBs and unscheduled Tel1 (ATM) activation, which in turn impairs checkpoint switch-off.","method":"ChIP, ssDNA accumulation assays, Rad53 phosphorylation, genetic analysis of mec1 and rad9 mutants","journal":"EMBO Journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP showing MRX persistence and Tel1 activation, genetic epistasis, multiple readouts, single lab","pmids":["24357557"],"is_preprint":false},{"year":2011,"finding":"In S. cerevisiae, Tel1 activation is enhanced by protein-bound DNA ends via the MRX complex. In vivo, Tel1 activation is increased in sae2Δ or mre11-3 mutants (defective in removing topoisomerase I from DNA) after camptothecin treatment. In vitro, tethering Fab fragments to DNA ends inhibits MRX-mediated end processing but enhances Tel1 activation.","method":"In vitro Tel1 kinase assay with Fab-tethered DNA ends, in vivo phosphorylation assays in sae2Δ and mre11-3 mutants","journal":"Molecular and Cellular Biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with defined DNA substrates plus in vivo genetic corroboration, two orthogonal approaches","pmids":["21402778"],"is_preprint":false},{"year":2015,"finding":"ATM forms a complex with Tankyrase 1 (TNKS1, a PAR polymerase), NuMA1, and BRCA1 during mitosis, independently of DNA damage. This complex is required for efficient poly(ADP-ribosyl)ation of NuMA1. A NuMA1 mutant non-phosphorylatable at ATM-dependent phosphorylation sites is poorly PARylated and induces loss of spindle bipolarity.","method":"Co-immunoprecipitation, immunofluorescence, mutagenesis of ATM phosphorylation sites in NuMA1, PARylation assay","journal":"Cell Cycle","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP identifying complex, mutagenesis of phosphosites with functional spindle readout, single lab","pmids":["24553124"],"is_preprint":false},{"year":2015,"finding":"ATM promotes HER2 protein stability by promoting a complex of HER2 with the chaperone HSP90, preventing HER2 ubiquitination and degradation. ATM sustains AKT activation downstream of HER2.","method":"Co-immunoprecipitation, ubiquitination assays, ATM knockdown/inhibition, in vitro and in vivo tumorigenicity assays","journal":"Nature Communications","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP identifying HER2-HSP90 complex promoted by ATM, ubiquitination assay showing reduced degradation, single lab","pmids":["25881002"],"is_preprint":false},{"year":2020,"finding":"ATM is found associated with lysosomes and physically interacts with the retrograde transport motor protein dynein. ATM kinase phosphorylates ATP6V1A (lysosomal proton pump). ATM loss causes enhanced retrograde lysosomal transport with perinuclear accumulation, impaired SLC2A4/GLUT4 plasma membrane translocation, and reduced glucose uptake.","method":"Co-immunoprecipitation of ATM with dynein, ATM kinase assay for ATP6V1A, lysosomal fractionation, live-cell imaging, glucose uptake assay in atm-null neurons","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP and kinase assay identifying novel substrates and interaction partners, functional readouts in ATM-null neurons, single lab","pmids":["32757690"],"is_preprint":false},{"year":2015,"finding":"KAT5 (Tip60) acetyltransferase is responsible for acetylation and activation of ATM in response to formaldehyde-induced chromatin damage during S phase. KAT5 and ATM are equally important for triggering the intra-S-phase checkpoint. ATM activation by formaldehyde did not require MRE11.","method":"KAT5 inhibition/knockdown, ATM activation assays (pS1981), acetylation assays, intra-S-phase checkpoint assay, MRE11 inhibition","journal":"Nucleic Acids Research","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — functional knockdown with ATM activation readout, mechanistic dissection separating KAT5 from MRE11 pathway, single lab","pmids":["26420831"],"is_preprint":false},{"year":2015,"finding":"Nuclear GIT2 is phosphorylated by ATM kinase following DNA damage. GIT2 is rapidly recruited to DNA double-strand breaks in an H2AX-, ATM-, and MRE11-dependent but MDC1- and RNF8-independent manner. GIT2 forms complexes with multiple DDR-associated factors and promotes DNA repair through stabilization of BRCA1.","method":"In vitro ATM kinase assay, Co-immunoprecipitation, laser microirradiation/recruitment assay, GIT2 knockout mice, BRCA1 stabilization assay","journal":"Molecular and Cellular Biology","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — in vitro kinase assay plus cellular localization with genetic dissection, Co-IP, KO mouse, single lab","pmids":["25605334"],"is_preprint":false},{"year":2000,"finding":"In the developing mouse nervous system, Atm is essential for ionizing radiation-induced apoptosis in select postmitotic neural populations. ATM-dependent apoptosis requires p53, and the proapoptotic effector Bax is required for most (but not all) ATM-dependent apoptosis, defining an ATM→p53→Bax apoptotic cascade in differentiating neural cells.","method":"Genetic epistasis with Atm-/-, p53-/-, and Bax-/- mouse models, TUNEL assay for apoptosis after irradiation","journal":"Apoptosis","confidence":"High","confidence_rationale":"Tier 2 / Strong — triple genetic epistasis (ATM, p53, Bax) with clear pathway ordering in vivo, replicated across multiple mouse models","pmids":["11303911"],"is_preprint":false},{"year":2007,"finding":"A FRET-based biosensor using an ATM phosphorylation site and an FHA phosphospecific binding domain measures ATM kinase activity in single living cells. The reporter responds to DSBs and is specific for ATM over ATR or DNA-PK.","method":"CFP-YFP FRET biosensor in living cells, ATM/ATR/DNA-PK specificity testing","journal":"DNA Repair","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — FRET biosensor with specificity controls distinguishing ATM from ATR and DNA-PK, single lab, tool development paper","pmids":["17428747"],"is_preprint":false},{"year":1997,"finding":"ATM co-localizes with RPA along synapsed meiotic chromosomes and at sites where interhomologous DNA interactions occur during meiotic prophase. In Atm-/- spermatocytes, RPA is present along synapsing chromosomes and at SC fragmentation sites, suggesting a functional interaction between ATM and RPA at meiotic recombination sites.","method":"Immunolocalization on meiotic chromosome spreads from Atm-/- and wild-type mice, co-localization analysis","journal":"Nature Genetics","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — immunolocalization demonstrating co-localization at defined chromosomal sites, Atm-null comparison, replicated across multiple specimens","pmids":["9398850"],"is_preprint":false}],"current_model":"ATM is a PI3K-like serine/threonine protein kinase that exists as an inactive dimer in resting cells, held inactive through FAT domain-mediated inter-subunit contacts that occlude substrate access; DNA double-strand breaks trigger recruitment via the MRE11-RAD50-NBS1/XRS2 complex (which requires ATP-bound Rad50 conformation and long nucleosome-free DNA), leading to intermolecular autophosphorylation at Ser1981 and dimer dissociation into active monomers, while oxidative stress independently activates ATM through disulfide-crosslinked dimer formation requiring a specific cysteine residue; active ATM phosphorylates a broad range of substrates—including CHK2, p53, H2AX, NBS1, RASSF1A, NCOA4, and ATP6V1A—to coordinate DSB repair, cell cycle checkpoints, apoptosis (via a p53-Bax cascade), ferritinophagy/ferroptosis, lysosomal trafficking, and telomere maintenance; NBS1 and ATMIN compete for ATM binding to direct signaling toward DSB-induced versus chromatin-stress-induced pathways respectively; cofactors including FOXO3a, KAT5/Tip60 (which acetylates ATM), UFL1 (which ufmylates histone H4), and the chromatin-remodeling E3 ligases RNF8/Chfr modulate ATM activation efficiency; and in mitosis ATM forms a non-DDR complex with Tankyrase1, NuMA1, and BRCA1 to support bipolar spindle structure through NuMA1 PARylation."},"narrative":{"mechanistic_narrative":"ATM is a PI3K-like serine/threonine protein kinase that serves as the apical sensor and signal transducer of DNA double-strand breaks (DSBs) and related genome-destabilizing stresses, coordinating cell-cycle checkpoints, DSB repair, apoptosis, and telomere maintenance [PMID:12556884, PMID:16327781, PMID:8553072]. In resting cells ATM is held catalytically inactive as a head-to-head homodimer in which FAT- and kinase-domain inter-subunit contacts, together with the N-terminal helical solenoid and the PIKK regulatory insert, sterically occlude substrate access [PMID:27229179, PMID:27097373, PMID:31740029]; DNA damage triggers intermolecular autophosphorylation at Ser1981 and dimer dissociation into active monomers [PMID:12556884]. Activation at breaks is driven by the MRE11-RAD50-NBS1/XRS2 (MRN/MRX) complex, which recruits ATM to DNA ends through the Xrs2/NBS1 C-terminus and requires an ATP-bound, closed Rad50 conformation and long nucleosome-free DNA rather than the break terminus itself [PMID:12923051, PMID:31073030, PMID:30698745, PMID:21402778]; oxidative stress independently activates ATM through a distinct disulfide-crosslinked dimer dependent on a critical cysteine, bypassing MRN [PMID:20966255]. Once active, ATM phosphorylates a broad substrate network—CHK2/Rad53, p53, RASSF1A, NCOA4, ATP6V1A, GIT2, and the telomere protein Ccq1—to enact checkpoint signaling, an ATM→p53→Bax apoptotic cascade in neural cells, ferritinophagy/ferroptosis, lysosomal transport, and telomerase recruitment [PMID:8553072, PMID:36752571, PMID:22302936, PMID:19962312, PMID:32757690, PMID:25605334, PMID:11303911]. Cofactor competition between NBS1 and ATMIN partitions ATM output toward DSB-induced versus chromatin-stress pathways [PMID:23219553], while chromatin modifiers KAT5/Tip60 acetylation, UFL1-dependent histone H4 ufmylation, and RNF8/Chfr ubiquitin ligases tune activation efficiency [PMID:30886146, PMID:21706008, PMID:26420831]. Beyond the DNA-damage response, ATM also acts in mitosis within a non-DDR complex with Tankyrase1, NuMA1, and BRCA1 to support bipolar spindle structure via NuMA1 PARylation [PMID:24553124].","teleology":[{"year":1996,"claim":"Established that the ATM family kinases sit at the apex of DNA-damage signaling by placing the checkpoint effector kinase Rad53 downstream of them, defining a kinase relay rather than a single sensor.","evidence":"Genetic suppressor screen and phosphorylation assays of TEL1/MEC1 controlling Rad53p in budding yeast","pmids":["8553072"],"confidence":"High","gaps":["Did not resolve the direct substrate of Tel1 versus Mec1","Mammalian ATM substrate identity not established here"]},{"year":1997,"claim":"Localized ATM physically to sites of meiotic recombination, extending its role from somatic damage signaling to programmed recombination intermediates.","evidence":"Immunolocalization of ATM with RPA on meiotic chromosome spreads from Atm-/- and wild-type mice","pmids":["9398850"],"confidence":"Medium","gaps":["Co-localization does not establish direct phosphorylation of RPA or recombination factors","Functional consequence at recombination sites not dissected"]},{"year":1999,"claim":"Defined how ATM signaling is terminated and pharmacologically overridden—caspase cleavage during apoptosis and direct caffeine inhibition both abolish kinase activity.","evidence":"In vitro caspase-3 cleavage and caffeine kinase-inhibition assays with in vivo Cds1/Chk2 readouts","pmids":["10454555","10531013"],"confidence":"High","gaps":["Caffeine's selectivity over related PIKKs not fully defined","Physiological role of apoptotic ATM cleavage uncertain"]},{"year":2001,"claim":"Identified the Mre11 complex as the upstream damage sensor required for Tel1/ATM-dependent checkpoint activation, linking break detection to kinase output in mitotic and meiotic cells.","evidence":"Genetic epistasis, Rad53 phosphorylation, and Co-IP in S. cerevisiae","pmids":["11430828"],"confidence":"High","gaps":["Mechanism by which MRX activates the kinase not resolved","Distinction between sensing and recruitment unclear"]},{"year":2003,"claim":"Resolved the core activation switch—ATM is an inactive dimer whose intermolecular Ser1981 autophosphorylation drives monomerization and kinase activation, and showed activation responds to chromatin changes rather than direct DNA-end binding.","evidence":"Phosphospecific antibody, Co-IP, kinase assays, and S1981 mutagenesis in irradiated human cells; ChIP localization of Tel1 via Xrs2 C-terminus in yeast","pmids":["12556884","12923051"],"confidence":"High","gaps":["How chromatin perturbation is transmitted to the dimer not defined","S1981 autophosphorylation later shown insufficient as sole trigger in some systems"]},{"year":2005,"claim":"Ordered ATM relative to ATR, showing ATM plus Mre11 nuclease processes DSBs into RPA-ssDNA to license ATR-Chk1 signaling in S/G2, establishing crosstalk between the two apical kinases.","evidence":"Epistasis with ATM inhibitor and Mre11 nuclease mutants, ChIP, Chk1 phosphorylation in cell-cycle-staged cells","pmids":["16327781"],"confidence":"High","gaps":["CDK-dependence mechanism of resection not detailed","Direct ATM substrates in the ATM-to-ATR handoff not enumerated"]},{"year":2009,"claim":"Revealed telomere-specific regulation of Tel1/ATM, with Rif1/Rif2 attenuating kinase recruitment by competing for the Xrs2 C-terminus, integrating ATM activity into telomere length homeostasis.","evidence":"ChIP, yeast two-hybrid, and Rif2/Xrs2 competition binding assays in S. cerevisiae","pmids":["19217405"],"confidence":"High","gaps":["Mammalian shelterin equivalence of Rif1/Rif2 competition not addressed here"]},{"year":2009,"claim":"Expanded the ATM substrate repertoire into tumor-suppressor signaling by identifying RASSF1A Ser131 phosphorylation that engages the MST2/LATS1/p73 axis.","evidence":"In vivo phosphorylation, Ser131 mutagenesis, and downstream kinase/p73 stabilization assays","pmids":["19962312"],"confidence":"Medium","gaps":["Single-lab substrate assignment without reciprocal in vitro confirmation noted in narrative","Quantitative contribution to checkpoint output unclear"]},{"year":2011,"claim":"Showed that chromatin-modifying E3 ligases RNF8 and Chfr gate ATM activation through histone ubiquitination and H4K16 acetylation, connecting chromatin relaxation to kinase activation efficiency.","evidence":"RNF8/Chfr double-knockout mouse model with kinase activity and histone modification readouts","pmids":["21706008"],"confidence":"Medium","gaps":["Direct effect of chromatin relaxation on the ATM dimer not mechanistically traced","Single lab"]},{"year":2011,"claim":"Demonstrated that protein-bound or blocked DNA ends and Tel1-promoted MRX retention regulate the balance between end-processing and kinase activation, and that ATM feedback shapes end-tethering for repair.","evidence":"In vitro Tel1 kinase assays with Fab-tethered DNA, ChIP, and DSB repair/end-tethering assays in yeast","pmids":["21402778","26901759"],"confidence":"High","gaps":["Relationship between activation and resection in mammalian cells not directly tested"]},{"year":2010,"claim":"Uncovered a DNA-damage-independent activation route—oxidative stress activates ATM via a distinct disulfide-crosslinked dimer requiring a specific cysteine, separating redox sensing from MRN-dependent break signaling.","evidence":"In vitro kinase reconstitution, non-reducing gels, and cysteine mutagenesis","pmids":["20966255"],"confidence":"High","gaps":["Physiological redox triggers and downstream redox-specific substrates not fully mapped"]},{"year":2012,"claim":"Defined how ATM pathway choice is encoded—NBS1 and ATMIN competitively bind ATM to route signaling to DSB versus chromatin-stress responses.","evidence":"Reciprocal Co-IP and NBS1/ATMIN single and double genetic deletions with substrate phosphorylation readouts","pmids":["23219553"],"confidence":"High","gaps":["Structural basis of competitive binding to ATM not resolved","Cofactor-specific substrate selectivity unclear"]},{"year":2012,"claim":"Established a direct telomere-maintenance function—Tel1/ATM phosphorylates Ccq1 Thr93 to recruit telomerase, linking kinase activity to telomere elongation.","evidence":"In vitro kinase assay, T93A phosphosite mutagenesis, telomerase ChIP, telomere length analysis in fission yeast","pmids":["22302936"],"confidence":"High","gaps":["Mammalian counterpart of Ccq1 phosphorylation not addressed"]},{"year":2015,"claim":"Identified non-DDR mitotic and chromatin-acetylation roles for ATM, including a Tankyrase1-NuMA1-BRCA1 spindle complex and KAT5/Tip60-mediated acetylation that activates ATM during S-phase formaldehyde damage independently of MRE11.","evidence":"Co-IP, phosphosite mutagenesis with spindle/PARylation readouts; KAT5 knockdown with ATM activation and acetylation assays","pmids":["24553124","26420831"],"confidence":"Medium","gaps":["Mechanistic link between acetylation and dimer dissociation not detailed","Single-lab findings for each"]},{"year":2015,"claim":"Revealed meiotic DSB interference as an ATM kinase function, with Tel1 suppressing adjacent break formation to space recombination events.","evidence":"Spo11-oligonucleotide mapping and kinase-dead tel1 analysis in yeast meiosis","pmids":["25539084"],"confidence":"High","gaps":["Substrate(s) mediating interference not identified"]},{"year":2016,"claim":"Provided the structural basis of autoinhibition—cryo-EM and single-particle EM of the ATM/Tel1 homodimer showed FAT/kinase inter-subunit contacts and HEAT-repeat packing bury active sites and block substrate access.","evidence":"Cryo-EM of S. pombe Tel1 and single-particle EM of human ATM with mTOR-based fitting","pmids":["27229179","27097373"],"confidence":"High","gaps":["Conformational transition to the active monomer not captured","Resolution limits in human EM map"]},{"year":2019,"claim":"Resolved the molecular requirements for MRX-dependent activation—an ATP-bound closed Mre11-Rad50 conformation, Rad50 ATPase activity, and long nucleosome-free DNA drive Tel1 activation independent of DNA termini, with nucleotide-bound Tel1 structures explaining substrate-access restriction.","evidence":"In vitro reconstitution with purified components, separation-of-function MR alleles, molecular dynamics, and cryo-EM of nucleotide-bound Tel1","pmids":["31073030","30698745","31740029"],"confidence":"High","gaps":["How the closed MR conformation allosterically opens the kinase not visualized","Mammalian reconstitution not shown"]},{"year":2019,"claim":"Linked ufmylation to ATM activation—UFL1 recruited by MRN monoufmylates histone H4 to license Tip60/Suv39h1 recruitment, MRE11 K282 ufmylation supports MRN assembly, and ATM phosphorylation of UFL1 forms a positive feedback loop.","evidence":"Co-IP, ChIP, in vitro ufmylation, ATM kinase assays, and mutagenesis (MRE11 K282R, cancer-associated G285C)","pmids":["30886146","30783677"],"confidence":"Medium","gaps":["Stoichiometry and kinetics of the feedback loop unclear","Single-lab findings"]},{"year":2019,"claim":"Extended ATM into iron metabolism and ferroptosis—ATM phosphorylates NCOA4 to sustain ferritinophagy and labile iron availability required for ferroptosis, largely independent of p53.","evidence":"Pharmacological inhibition, ATM/Trp53 CRISPR knockouts, ferritinophagy and iron assays, NCOA4 phosphorylation","pmids":["36752571"],"confidence":"Medium","gaps":["NCOA4 phosphosite(s) not mapped","Direct versus indirect phosphorylation not fully distinguished"]},{"year":2020,"claim":"Defined a cytoplasmic, lysosomal role for ATM—association with dynein and phosphorylation of the lysosomal proton pump ATP6V1A regulate retrograde lysosomal transport, GLUT4 trafficking, and glucose uptake.","evidence":"Co-IP, ATP6V1A kinase assay, lysosomal fractionation, live imaging, glucose uptake in atm-null neurons","pmids":["32757690"],"confidence":"Medium","gaps":["How nuclear-damage-responsive ATM partitions to lysosomes unclear","Single lab"]},{"year":null,"claim":"It remains unresolved how the distinct activation inputs (MRN/ATP-bound MR, oxidation, acetylation, ufmylation, cofactor competition) are mechanistically integrated into the conformational opening of the autoinhibited dimer, and how ATM substrate selectivity is encoded across its nuclear, telomeric, mitotic, and cytoplasmic functions.","evidence":"","pmids":[],"confidence":"High","gaps":["No structure of the activated ATM monomer bound to a physiological substrate","Substrate-targeting rules for divergent pathways not defined","Integration of redox and break-induced activation states unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,2,9,18,20,30,32]},{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[22,23,15]},{"term_id":"GO:0140299","term_label":"molecular sensor activity","supporting_discovery_ids":[1]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[21,29]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,8,32]},{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[30]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[6,35,19]}],"pathway":[{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[0,2,6,22,23,32]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[2,3,5]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[7,33,9]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[1,31]},{"term_id":"R-HSA-1474165","term_label":"Reproduction","supporting_discovery_ids":[19,35]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[10,12,31]}],"complexes":["MRN/MRX complex (associated activator)","ATM-Tankyrase1-NuMA1-BRCA1 mitotic complex"],"partners":["NBS1","ATMIN","MRE11","RAD50","FOXO3A","KAT5","UFL1","BRCA1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q13315","full_name":"Serine-protein kinase ATM","aliases":["Ataxia telangiectasia mutated","A-T mutated"],"length_aa":3056,"mass_kda":350.7,"function":"Serine/threonine protein kinase which activates checkpoint signaling upon double strand breaks (DSBs), apoptosis and genotoxic stresses such as ionizing ultraviolet A light (UVA), thereby acting as a DNA damage sensor (PubMed:10550055, PubMed:10839545, PubMed:10910365, PubMed:12556884, PubMed:14871926, PubMed:15064416, PubMed:15448695, PubMed:15456891, PubMed:15790808, PubMed:15916964, PubMed:17923702, PubMed:21757780, PubMed:24534091, PubMed:35076389, PubMed:9733514). Recognizes the substrate consensus sequence [ST]-Q (PubMed:10550055, PubMed:10839545, PubMed:10910365, PubMed:12556884, PubMed:14871926, PubMed:15448695, PubMed:15456891, PubMed:15916964, PubMed:17923702, PubMed:24534091, PubMed:9733514). Phosphorylates 'Ser-139' of histone variant H2AX at double strand breaks (DSBs), thereby regulating DNA damage response mechanism (By similarity). Also plays a role in pre-B cell allelic exclusion, a process leading to expression of a single immunoglobulin heavy chain allele to enforce clonality and monospecific recognition by the B-cell antigen receptor (BCR) expressed on individual B-lymphocytes. After the introduction of DNA breaks by the RAG complex on one immunoglobulin allele, acts by mediating a repositioning of the second allele to pericentromeric heterochromatin, preventing accessibility to the RAG complex and recombination of the second allele. Also involved in signal transduction and cell cycle control. May function as a tumor suppressor. Necessary for activation of ABL1 and SAPK. Phosphorylates DYRK2, CHEK2, p53/TP53, FBXW7, FANCD2, NFKBIA, BRCA1, CREBBP/CBP, RBBP8/CTIP, FBXO46, MRE11, nibrin (NBN), RAD50, RAD17, PELI1, TERF1, UFL1, RAD9, UBQLN4 and DCLRE1C (PubMed:10550055, PubMed:10766245, PubMed:10802669, PubMed:10839545, PubMed:10910365, PubMed:10973490, PubMed:11375976, PubMed:12086603, PubMed:15456891, PubMed:19965871, PubMed:21757780, PubMed:24534091, PubMed:26240375, PubMed:26774286, PubMed:30171069, PubMed:30612738, PubMed:30886146, PubMed:30952868, PubMed:38128537, PubMed:9733515, PubMed:9843217). May play a role in vesicle and/or protein transport. Could play a role in T-cell development, gonad and neurological function. Plays a role in replication-dependent histone mRNA degradation. Binds DNA ends. Phosphorylation of DYRK2 in nucleus in response to genotoxic stress prevents its MDM2-mediated ubiquitination and subsequent proteasome degradation (PubMed:19965871). Phosphorylates ATF2 which stimulates its function in DNA damage response (PubMed:15916964). Phosphorylates ERCC6 which is essential for its chromatin remodeling activity at DNA double-strand breaks (PubMed:29203878). Phosphorylates TTC5/STRAP at 'Ser-203' in the cytoplasm in response to DNA damage, which promotes TTC5/STRAP nuclear localization (PubMed:15448695). Also involved in pexophagy by mediating phosphorylation of PEX5: translocated to peroxisomes in response to reactive oxygen species (ROS), and catalyzes phosphorylation of PEX5, promoting PEX5 ubiquitination and induction of pexophagy (PubMed:26344566)","subcellular_location":"Nucleus; Cytoplasmic vesicle; Cytoplasm, cytoskeleton, microtubule organizing center, centrosome; Peroxisome matrix","url":"https://www.uniprot.org/uniprotkb/Q13315/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ATM","classification":"Not Classified","n_dependent_lines":20,"n_total_lines":1208,"dependency_fraction":0.016556291390728478},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000149311","cell_line_id":"CID001127","localizations":[{"compartment":"nucleoplasm","grade":3},{"compartment":"nuclear_punctae","grade":1}],"interactors":[],"url":"https://opencell.sf.czbiohub.org/target/CID001127","total_profiled":1310},"omim":[{"mim_id":"621534","title":"FAMILY WITH SEQUENCE SIMILARITY 135, MEMBER B; FAM135B","url":"https://www.omim.org/entry/621534"},{"mim_id":"620431","title":"FLYWCH-TYPE ZINC FINGER PROTEIN 1; FLYWCH1","url":"https://www.omim.org/entry/620431"},{"mim_id":"620226","title":"UBIQUITIN-SPECIFIC PEPTIDASE 37; USP37","url":"https://www.omim.org/entry/620226"},{"mim_id":"619870","title":"COILED-COIL DOMAIN-CONTAINING PROTEIN 82; CCDC82","url":"https://www.omim.org/entry/619870"},{"mim_id":"619222","title":"SUPPRESSOR OF CANCER CELL INVASION; SCAI","url":"https://www.omim.org/entry/619222"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Vesicles","reliability":"Supported"},{"location":"Golgi apparatus","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/ATM"},"hgnc":{"alias_symbol":["TEL1","TELO1"],"prev_symbol":["ATA","ATDC","ATC","ATD"]},"alphafold":{"accession":"Q13315","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13315","model_url":"","pae_url":"","plddt_mean":null},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ATM","jax_strain_url":"https://www.jax.org/strain/search?query=ATM"},"sequence":{"accession":"Q13315","fasta_url":"https://rest.uniprot.org/uniprotkb/Q13315.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q13315/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13315"}},"corpus_meta":[{"pmid":"12556884","id":"PMC_12556884","title":"DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation.","date":"2003","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/12556884","citation_count":2671,"is_preprint":false},{"pmid":"20966255","id":"PMC_20966255","title":"ATM activation by oxidative stress.","date":"2010","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/20966255","citation_count":901,"is_preprint":false},{"pmid":"16327781","id":"PMC_16327781","title":"ATM- and cell cycle-dependent regulation of ATR in response to DNA double-strand breaks.","date":"2005","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/16327781","citation_count":870,"is_preprint":false},{"pmid":"11252893","id":"PMC_11252893","title":"The many substrates and functions of ATM.","date":"2000","source":"Nature reviews. 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DNA damage induces rapid intermolecular autophosphorylation of serine 1981, causing dimer dissociation and initiating ATM kinase activity. ATM activation does not require direct binding to DNA strand breaks but may result from changes in chromatin structure.\",\n      \"method\": \"Phosphospecific antibody detection, immunoprecipitation, kinase activity assays, irradiation with defined doses\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods (phosphospecific antibody, Co-IP, in vitro kinase assay, site-directed mutagenesis of S1981), widely replicated finding\",\n      \"pmids\": [\"12556884\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"ATM can be directly activated by oxidative stress in the absence of DNA double-strand breaks and the MRN complex. Oxidized ATM forms a disulfide-cross-linked dimer distinct from the inactive dimer seen in unirradiated cells. Mutation of a critical cysteine residue involved in disulfide bond formation specifically blocked activation through the oxidation pathway.\",\n      \"method\": \"In vitro kinase assay, non-reducing gel electrophoresis, cysteine mutagenesis, cell-based activation assays\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstitution in vitro, mutagenesis of critical cysteine, multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"20966255\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"ATM and the nuclease activity of Mre11 are required for processing DNA double-strand breaks to generate RPA-coated ssDNA needed for ATR recruitment and subsequent Chk1 phosphorylation. ATM-dependent ATR activation in response to DSBs is restricted to S and G2 cell cycle phases and requires CDK kinase activity.\",\n      \"method\": \"Epistasis analysis with ATM inhibitor and Mre11 nuclease mutants, ChIP, immunofluorescence, flow cytometry, Chk1 phosphorylation assay\",\n      \"journal\": \"Nature Cell Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis combined with biochemical readouts, pathway ordering demonstrated with multiple complementary approaches\",\n      \"pmids\": [\"16327781\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"In S. cerevisiae, the ATM homolog TEL1 and the ATR homolog MEC1 have overlapping functions in response to DNA damage and replication blocks. Both MEC1 and TEL1 control phosphorylation of Rad53p (the RAD53/SAD1 checkpoint kinase) in response to DNA damage, placing RAD53 as a signal transducer downstream of these two kinases.\",\n      \"method\": \"Genetic suppressor screen, phosphorylation assays, overexpression studies in yeast\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis with suppressor screen plus direct phosphorylation readout, foundational pathway-ordering result replicated by many subsequent studies\",\n      \"pmids\": [\"8553072\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"In S. cerevisiae, Tel1 (ATM homolog) and the Mre11 complex define a DNA damage checkpoint pathway. The Tel1-Mre11 complex pathway activates Rad53 and its interaction with Rad9 in mitotic cells, while in meiosis it acts via Rad9 and Mek1. Activation depends on the Mre11 complex as a damage sensor and on unprocessed DSBs.\",\n      \"method\": \"Genetic epistasis, Rad53 phosphorylation assays, co-immunoprecipitation, meiotic and mitotic checkpoint analysis in yeast\",\n      \"journal\": \"Molecular Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis with multiple checkpoint readouts, reciprocal interaction studies, consistent with mammalian ATM/MRN pathway\",\n      \"pmids\": [\"11430828\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"ATM kinase activity is directly inhibited by caffeine in vitro, and caffeine inhibits radiation-induced activation of Cds1/Chk2 in vivo. This provides a molecular explanation for caffeine's ability to override DNA-damage checkpoint responses.\",\n      \"method\": \"In vitro ATM kinase assay with caffeine, in vivo Cds1 phosphorylation assay\",\n      \"journal\": \"Current Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct in vitro kinase assay plus in vivo corroboration, single lab but two orthogonal methods\",\n      \"pmids\": [\"10531013\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"In budding yeast, Tel1 (ATM homolog) associates with DNA double-strand breaks through a mechanism dependent on the C terminus of Xrs2 (Nbs1 homolog). This association is required for activation of DNA damage responses including cell survival and Rad53 phosphorylation.\",\n      \"method\": \"ChIP of Tel1 at DSBs, C-terminal truncation of Xrs2, Rad53 phosphorylation assays\",\n      \"journal\": \"Genes & Development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP demonstrating direct DSB association, genetic dissection of Xrs2 C-terminus requirement, functional readouts\",\n      \"pmids\": [\"12923051\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"ATM is specifically cleaved and inactivated during apoptosis in a caspase-dependent manner. ATM is an efficient substrate for caspase-3 but not caspase-6 in vitro. Apoptotic cleavage of ATM abrogates its protein kinase activity against p53 but has no apparent effect on DNA binding properties of ATM.\",\n      \"method\": \"In vitro caspase cleavage assays, in vivo apoptosis induction with multiple stimuli, ATM kinase assay, DNA-binding assay\",\n      \"journal\": \"Molecular and Cellular Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro reconstitution with purified caspase-3, in vivo corroboration, multiple apoptotic stimuli tested, kinase and DNA-binding assays performed\",\n      \"pmids\": [\"10454555\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"FOXO3a interacts with ATM to promote phosphorylation of ATM at Ser1981 and downstream mediator nuclear foci formation in response to DNA damage. The C-terminal domain of FOXO3a binds to the FAT domain of ATM. Silencing FOXO3a abrogates ATM-pS1981 and phospho-H2AX foci after DNA damage; increasing FOXO3a promotes ATM-regulated signaling and DNA repair.\",\n      \"method\": \"Co-immunoprecipitation, FOXO3a knockdown/overexpression, immunofluorescence for ATM-pS1981 and γH2AX foci, cell cycle checkpoint assays\",\n      \"journal\": \"Nature Cell Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — reciprocal Co-IP plus functional knockdown/overexpression with multiple readouts, single lab\",\n      \"pmids\": [\"18344987\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ATM phosphorylates NCOA4, facilitating NCOA4-ferritin interaction and sustaining ferritinophagy (selective autophagic degradation of ferritin). This phosphorylation by ATM dominates intracellular labile free iron availability and is required for ferroptosis execution. ATM ablation-induced ferroptotic resistance is largely independent of TRP53.\",\n      \"method\": \"Pharmacological ATM inhibition, genetic ATM/Trp53 knockout (CRISPR), ferritinophagy assays, iron measurement, phosphorylation assays for NCOA4\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — genetic knockout combined with biochemical phosphorylation assay and ferritinophagy readout, single lab\",\n      \"pmids\": [\"36752571\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"UFL1 (ufmylation E3 ligase) is recruited to DSBs by the MRE11/RAD50/NBS1 complex and monoufmylates histone H4 following DNA damage. Monoufmylated histone H4 promotes Suv39h1 and Tip60 recruitment to enable ATM activation. ATM phosphorylates UFL1 at serine 462, enhancing UFL1 E3 ligase activity and forming a positive feedback loop for ATM activation.\",\n      \"method\": \"Co-immunoprecipitation, ChIP, in vitro ufmylation assay, ATM kinase assay, knockdown experiments\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — multiple biochemical assays including in vitro reconstitution steps, single lab, Co-IP and ChIP\",\n      \"pmids\": [\"30886146\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"MRE11 is UFMylated on K282, and this modification is required for MRN complex formation under unperturbed conditions and for DSB-induced optimal ATM activation. A cancer-associated mutation MRE11(G285C) phenocopies the UFMylation-defective mutant MRE11(K282R), impairing ATM activation.\",\n      \"method\": \"Site-directed mutagenesis, Co-immunoprecipitation, ATM activation assays (pS1981), homologous recombination assays\",\n      \"journal\": \"Nucleic Acids Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — mutagenesis of specific lysine combined with functional ATM activation readout and Co-IP, single lab\",\n      \"pmids\": [\"30783677\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"RNF8 and Chfr E3 ubiquitin ligases synergistically regulate histone ubiquitination to control histone H4 Lys16 acetylation through MRG15-dependent acetyltransferase complexes, thereby controlling chromatin relaxation and ATM activation following DNA damage. Loss of both RNF8 and Chfr suppresses DNA damage-induced ATM kinase activation.\",\n      \"method\": \"Double-knockout mouse model, immunofluorescence, kinase activity assays, histone modification analysis, in vivo tumor development\",\n      \"journal\": \"Nature Structural & Molecular Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic double-knockout with biochemical readouts, in vivo mouse model, single lab\",\n      \"pmids\": [\"21706008\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Cryo-EM structure of intact homodimeric ATM/Tel1 from S. pombe reveals that two monomers contact head-to-head through FAT and kinase domains. The N-terminal helical solenoid tightly packs against FAT and kinase domains. The dimer interface and consecutive HEAT repeats inhibit binding of kinase substrates and regulators by steric hindrance.\",\n      \"method\": \"Cryo-EM single-particle reconstruction of full-length ATM/Tel1\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — cryo-EM structure of intact complex providing direct structural evidence for inhibition mechanism, single lab but high-resolution method\",\n      \"pmids\": [\"27229179\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Single-particle electron microscopy of human dimeric ATM reveals that in the dimeric resting state, the active sites are buried, restricting substrate access. The N-terminal and C-terminal regions of ATM were localized by fitting of mTOR crystal structure into the EM map.\",\n      \"method\": \"Single-particle electron microscopy, structural fitting with mTOR crystal structure\",\n      \"journal\": \"Cell Cycle\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — EM structural data from single lab, resolution limited; structural conclusions consistent with other ATM structural studies\",\n      \"pmids\": [\"27097373\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Cryo-EM structure of nucleotide-bound Tel1 (ATM ortholog) reveals that catalytic residues are in a productive conformation for catalysis, but the PIKK regulatory domain insert restricts peptide substrate access and the N-lobe is in an open conformation, explaining the requirement for Tel1 activation. Structural comparisons suggest a conserved allosteric activation mechanism among PIKKs.\",\n      \"method\": \"Cryo-EM structure determination of nucleotide-bound Tel1\",\n      \"journal\": \"Structure\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — high-resolution cryo-EM with nucleotide bound providing mechanistic insight into substrate access restriction, single lab but rigorous structural method\",\n      \"pmids\": [\"31740029\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"In S. cerevisiae, telomeric proteins Rif1 and Rif2 attenuate Tel1 recruitment to DNA ends through distinct mechanisms. Rif2 competes with Tel1 for binding to the C terminus of Xrs2, thereby preventing Tel1 localization to DNA ends. Once Tel1 is delocalized, MRX does not associate efficiently with Rap1-covered DNA ends.\",\n      \"method\": \"ChIP at telomeres, yeast two-hybrid, genetic epistasis, Rif2/Xrs2 binding competition assays\",\n      \"journal\": \"Molecular Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP demonstrating Tel1 localization changes, direct competition binding assay showing Rif2 and Tel1 compete for Xrs2 C-terminus, multiple complementary methods\",\n      \"pmids\": [\"19217405\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"S. cerevisiae Tel2 interacts with Tel1 and is specifically required for Tel1 localization to a DNA break and its activation of downstream targets, even when Tel1 protein levels are high. Computational analysis revealed structural homology between Tel2 and Ddc2 (ATRIP), suggesting a common structural principle for partners of PI3K-like kinases.\",\n      \"method\": \"Co-immunoprecipitation, ChIP at DSBs, genetic analysis, computational structural analysis\",\n      \"journal\": \"Genes & Development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP plus ChIP demonstrating localization requirement, functional readout of downstream targets, single lab\",\n      \"pmids\": [\"18334620\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Tel1 (ATM ortholog) and Rad3 (ATR ortholog) in fission yeast phosphorylate the telomere protein Ccq1 at Thr93. This phosphorylation is required for telomerase recruitment to telomeres; a ccq1-T93A mutant fails to recruit telomerase and shows gradual telomere shortening.\",\n      \"method\": \"In vitro kinase assay with purified Tel1/Rad3, phosphosite mutagenesis (T93A), telomerase ChIP, telomere length analysis\",\n      \"journal\": \"Genes & Development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase assay demonstrating direct phosphorylation, mutagenesis showing phosphosite is essential for telomerase recruitment, two orthogonal readouts\",\n      \"pmids\": [\"22302936\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Tel1 (ATM) in S. cerevisiae mediates distance-dependent DSB interference in cis during meiosis, in which the occurrence of a DSB suppresses adjacent DSB formation. Loss of Tel1 causes DSBs to cluster within discrete zones, and Tel1 kinase activity is required for this suppression.\",\n      \"method\": \"Spo11-oligonucleotide mapping, kinase-dead tel1 mutation analysis, genetic epistasis in yeast meiosis\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — kinase-dead mutation distinguishes kinase-dependent effects, genome-wide Spo11-oligonucleotide mapping providing mechanistic insight, two orthogonal approaches\",\n      \"pmids\": [\"25539084\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"ATM phosphorylates RASSF1A on Ser131 in response to DNA damage, leading to activation of MST2 and LATS1 kinases and stabilization of p73. Polymorphism S131F in RASSF1A (at the ATM phosphorylation site) confers resistance to DNA-damaging agents.\",\n      \"method\": \"In vivo phosphorylation assay, site-directed mutagenesis of Ser131, kinase activity assays for MST2/LATS1, p73 stabilization assay\",\n      \"journal\": \"Current Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — mutagenesis of ATM phosphosite with functional pathway readout, single lab\",\n      \"pmids\": [\"19962312\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"NBS1 and ATMIN compete for ATM binding, controlling ATM signaling pathway choice. ATMIN is required for ATM signaling induced by chromatin stress but not DSBs (where NBS1 is required). Loss of one cofactor increases flux through the alternative pathway; NBS1/ATMIN double deficiency causes complete abrogation of ATM signaling.\",\n      \"method\": \"Co-immunoprecipitation, genetic deletion (atmin and nbs1 mutant cells), ATM substrate phosphorylation assays, radiosensitivity assays\",\n      \"journal\": \"Cell Reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP demonstrating competition, genetic double-knockout showing complete ATM pathway abrogation, multiple functional readouts\",\n      \"pmids\": [\"23219553\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Tel1 (ATM ortholog) activation requires Rad50 ATPase activity and long nucleosome-free DNA, but does not require DNA double-strand termini. Either Mre11 or Xrs2, but not both, is required in addition to DNA and Rad50. All three MRX subunits show physical association with Tel1.\",\n      \"method\": \"In vitro Tel1 kinase reconstitution with purified components, ATPase-dead Rad50 mutants, varying DNA substrates, physical binding assays\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — biochemical reconstitution with purified components, systematic dissection of requirements using mutants and varied substrates, single lab\",\n      \"pmids\": [\"31073030\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"The ATP-bound conformation of the Mre11-Rad50 (MR) complex is essential for Tel1/ATM activation. Separation-of-function alleles mre11-S499P and rad50-A78T specifically impair Tel1 activation by reducing Tel1-MRX interaction without impairing DSB repair. Molecular dynamics simulations show MR bound to ATP adopts a tightly closed conformation critical for Tel1 activation.\",\n      \"method\": \"Separation-of-function mutant analysis, ChIP for Tel1 at DSBs, Tel1 kinase assays, molecular dynamics simulations, Co-immunoprecipitation\",\n      \"journal\": \"Nucleic Acids Research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — separation-of-function mutations with direct Tel1 activation readout, ChIP, Co-IP, and computational structural analysis, multiple orthogonal methods\",\n      \"pmids\": [\"30698745\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"In S. cerevisiae, Tel1 promotes MRX retention at DSBs, which is important for end-tethering and DSB repair by both homologous recombination and NHEJ. Rif2, recruited to DSBs, counteracts Tel1's role in MRX accumulation and enhances ATP hydrolysis by MRX, attenuating MRX end-tethering function.\",\n      \"method\": \"ChIP, synthetic phenotype screen, DSB repair assays (HR and NHEJ), end-tethering assays, genetic epistasis\",\n      \"journal\": \"PLoS Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and functional repair assays, genetic epistasis, single lab\",\n      \"pmids\": [\"26901759\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Tel1 (ATM) promotes nucleolytic processing (resection) of telomeres by promoting MRX activity. The hyperactive Tel1-hy909 variant shows increased association at DSBs with telomeric repeats and increases persistence of MRX and Est1 at DSBs adjacent to telomeric repeats, accounting for increased telomere resection and elongation. Rif2 cannot inhibit processing at Tel1-hy909 telomeres.\",\n      \"method\": \"ChIP, telomere resection assays, telomere length analysis, gain-of-function tel1-hy909 mutant\",\n      \"journal\": \"Molecular and Cellular Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — ChIP and telomere functional assays, hyperactive mutant analysis, single lab\",\n      \"pmids\": [\"22354991\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"In S. cerevisiae, Mec1 (ATR ortholog) regulates resection of DSB ends, and loss of Mec1 accelerates resection by reducing Rad9 loading at DSBs. Extensive resection caused by Mec1 loss leads to prolonged MRX presence at DSBs and unscheduled Tel1 (ATM) activation, which in turn impairs checkpoint switch-off.\",\n      \"method\": \"ChIP, ssDNA accumulation assays, Rad53 phosphorylation, genetic analysis of mec1 and rad9 mutants\",\n      \"journal\": \"EMBO Journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP showing MRX persistence and Tel1 activation, genetic epistasis, multiple readouts, single lab\",\n      \"pmids\": [\"24357557\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"In S. cerevisiae, Tel1 activation is enhanced by protein-bound DNA ends via the MRX complex. In vivo, Tel1 activation is increased in sae2Δ or mre11-3 mutants (defective in removing topoisomerase I from DNA) after camptothecin treatment. In vitro, tethering Fab fragments to DNA ends inhibits MRX-mediated end processing but enhances Tel1 activation.\",\n      \"method\": \"In vitro Tel1 kinase assay with Fab-tethered DNA ends, in vivo phosphorylation assays in sae2Δ and mre11-3 mutants\",\n      \"journal\": \"Molecular and Cellular Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with defined DNA substrates plus in vivo genetic corroboration, two orthogonal approaches\",\n      \"pmids\": [\"21402778\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"ATM forms a complex with Tankyrase 1 (TNKS1, a PAR polymerase), NuMA1, and BRCA1 during mitosis, independently of DNA damage. This complex is required for efficient poly(ADP-ribosyl)ation of NuMA1. A NuMA1 mutant non-phosphorylatable at ATM-dependent phosphorylation sites is poorly PARylated and induces loss of spindle bipolarity.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence, mutagenesis of ATM phosphorylation sites in NuMA1, PARylation assay\",\n      \"journal\": \"Cell Cycle\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP identifying complex, mutagenesis of phosphosites with functional spindle readout, single lab\",\n      \"pmids\": [\"24553124\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"ATM promotes HER2 protein stability by promoting a complex of HER2 with the chaperone HSP90, preventing HER2 ubiquitination and degradation. ATM sustains AKT activation downstream of HER2.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, ATM knockdown/inhibition, in vitro and in vivo tumorigenicity assays\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP identifying HER2-HSP90 complex promoted by ATM, ubiquitination assay showing reduced degradation, single lab\",\n      \"pmids\": [\"25881002\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ATM is found associated with lysosomes and physically interacts with the retrograde transport motor protein dynein. ATM kinase phosphorylates ATP6V1A (lysosomal proton pump). ATM loss causes enhanced retrograde lysosomal transport with perinuclear accumulation, impaired SLC2A4/GLUT4 plasma membrane translocation, and reduced glucose uptake.\",\n      \"method\": \"Co-immunoprecipitation of ATM with dynein, ATM kinase assay for ATP6V1A, lysosomal fractionation, live-cell imaging, glucose uptake assay in atm-null neurons\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP and kinase assay identifying novel substrates and interaction partners, functional readouts in ATM-null neurons, single lab\",\n      \"pmids\": [\"32757690\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"KAT5 (Tip60) acetyltransferase is responsible for acetylation and activation of ATM in response to formaldehyde-induced chromatin damage during S phase. KAT5 and ATM are equally important for triggering the intra-S-phase checkpoint. ATM activation by formaldehyde did not require MRE11.\",\n      \"method\": \"KAT5 inhibition/knockdown, ATM activation assays (pS1981), acetylation assays, intra-S-phase checkpoint assay, MRE11 inhibition\",\n      \"journal\": \"Nucleic Acids Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — functional knockdown with ATM activation readout, mechanistic dissection separating KAT5 from MRE11 pathway, single lab\",\n      \"pmids\": [\"26420831\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Nuclear GIT2 is phosphorylated by ATM kinase following DNA damage. GIT2 is rapidly recruited to DNA double-strand breaks in an H2AX-, ATM-, and MRE11-dependent but MDC1- and RNF8-independent manner. GIT2 forms complexes with multiple DDR-associated factors and promotes DNA repair through stabilization of BRCA1.\",\n      \"method\": \"In vitro ATM kinase assay, Co-immunoprecipitation, laser microirradiation/recruitment assay, GIT2 knockout mice, BRCA1 stabilization assay\",\n      \"journal\": \"Molecular and Cellular Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — in vitro kinase assay plus cellular localization with genetic dissection, Co-IP, KO mouse, single lab\",\n      \"pmids\": [\"25605334\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"In the developing mouse nervous system, Atm is essential for ionizing radiation-induced apoptosis in select postmitotic neural populations. ATM-dependent apoptosis requires p53, and the proapoptotic effector Bax is required for most (but not all) ATM-dependent apoptosis, defining an ATM→p53→Bax apoptotic cascade in differentiating neural cells.\",\n      \"method\": \"Genetic epistasis with Atm-/-, p53-/-, and Bax-/- mouse models, TUNEL assay for apoptosis after irradiation\",\n      \"journal\": \"Apoptosis\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — triple genetic epistasis (ATM, p53, Bax) with clear pathway ordering in vivo, replicated across multiple mouse models\",\n      \"pmids\": [\"11303911\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"A FRET-based biosensor using an ATM phosphorylation site and an FHA phosphospecific binding domain measures ATM kinase activity in single living cells. The reporter responds to DSBs and is specific for ATM over ATR or DNA-PK.\",\n      \"method\": \"CFP-YFP FRET biosensor in living cells, ATM/ATR/DNA-PK specificity testing\",\n      \"journal\": \"DNA Repair\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — FRET biosensor with specificity controls distinguishing ATM from ATR and DNA-PK, single lab, tool development paper\",\n      \"pmids\": [\"17428747\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"ATM co-localizes with RPA along synapsed meiotic chromosomes and at sites where interhomologous DNA interactions occur during meiotic prophase. In Atm-/- spermatocytes, RPA is present along synapsing chromosomes and at SC fragmentation sites, suggesting a functional interaction between ATM and RPA at meiotic recombination sites.\",\n      \"method\": \"Immunolocalization on meiotic chromosome spreads from Atm-/- and wild-type mice, co-localization analysis\",\n      \"journal\": \"Nature Genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — immunolocalization demonstrating co-localization at defined chromosomal sites, Atm-null comparison, replicated across multiple specimens\",\n      \"pmids\": [\"9398850\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ATM is a PI3K-like serine/threonine protein kinase that exists as an inactive dimer in resting cells, held inactive through FAT domain-mediated inter-subunit contacts that occlude substrate access; DNA double-strand breaks trigger recruitment via the MRE11-RAD50-NBS1/XRS2 complex (which requires ATP-bound Rad50 conformation and long nucleosome-free DNA), leading to intermolecular autophosphorylation at Ser1981 and dimer dissociation into active monomers, while oxidative stress independently activates ATM through disulfide-crosslinked dimer formation requiring a specific cysteine residue; active ATM phosphorylates a broad range of substrates—including CHK2, p53, H2AX, NBS1, RASSF1A, NCOA4, and ATP6V1A—to coordinate DSB repair, cell cycle checkpoints, apoptosis (via a p53-Bax cascade), ferritinophagy/ferroptosis, lysosomal trafficking, and telomere maintenance; NBS1 and ATMIN compete for ATM binding to direct signaling toward DSB-induced versus chromatin-stress-induced pathways respectively; cofactors including FOXO3a, KAT5/Tip60 (which acetylates ATM), UFL1 (which ufmylates histone H4), and the chromatin-remodeling E3 ligases RNF8/Chfr modulate ATM activation efficiency; and in mitosis ATM forms a non-DDR complex with Tankyrase1, NuMA1, and BRCA1 to support bipolar spindle structure through NuMA1 PARylation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ATM is a PI3K-like serine/threonine protein kinase that serves as the apical sensor and signal transducer of DNA double-strand breaks (DSBs) and related genome-destabilizing stresses, coordinating cell-cycle checkpoints, DSB repair, apoptosis, and telomere maintenance [#0, #2, #3]. In resting cells ATM is held catalytically inactive as a head-to-head homodimer in which FAT- and kinase-domain inter-subunit contacts, together with the N-terminal helical solenoid and the PIKK regulatory insert, sterically occlude substrate access [#13, #14, #15]; DNA damage triggers intermolecular autophosphorylation at Ser1981 and dimer dissociation into active monomers [#0]. Activation at breaks is driven by the MRE11-RAD50-NBS1/XRS2 (MRN/MRX) complex, which recruits ATM to DNA ends through the Xrs2/NBS1 C-terminus and requires an ATP-bound, closed Rad50 conformation and long nucleosome-free DNA rather than the break terminus itself [#6, #22, #23, #27]; oxidative stress independently activates ATM through a distinct disulfide-crosslinked dimer dependent on a critical cysteine, bypassing MRN [#1]. Once active, ATM phosphorylates a broad substrate network—CHK2/Rad53, p53, RASSF1A, NCOA4, ATP6V1A, GIT2, and the telomere protein Ccq1—to enact checkpoint signaling, an ATM→p53→Bax apoptotic cascade in neural cells, ferritinophagy/ferroptosis, lysosomal transport, and telomerase recruitment [#3, #9, #18, #20, #30, #32, #33]. Cofactor competition between NBS1 and ATMIN partitions ATM output toward DSB-induced versus chromatin-stress pathways [#21], while chromatin modifiers KAT5/Tip60 acetylation, UFL1-dependent histone H4 ufmylation, and RNF8/Chfr ubiquitin ligases tune activation efficiency [#10, #12, #31]. Beyond the DNA-damage response, ATM also acts in mitosis within a non-DDR complex with Tankyrase1, NuMA1, and BRCA1 to support bipolar spindle structure via NuMA1 PARylation [#28].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Established that the ATM family kinases sit at the apex of DNA-damage signaling by placing the checkpoint effector kinase Rad53 downstream of them, defining a kinase relay rather than a single sensor.\",\n      \"evidence\": \"Genetic suppressor screen and phosphorylation assays of TEL1/MEC1 controlling Rad53p in budding yeast\",\n      \"pmids\": [\"8553072\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve the direct substrate of Tel1 versus Mec1\", \"Mammalian ATM substrate identity not established here\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Localized ATM physically to sites of meiotic recombination, extending its role from somatic damage signaling to programmed recombination intermediates.\",\n      \"evidence\": \"Immunolocalization of ATM with RPA on meiotic chromosome spreads from Atm-/- and wild-type mice\",\n      \"pmids\": [\"9398850\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Co-localization does not establish direct phosphorylation of RPA or recombination factors\", \"Functional consequence at recombination sites not dissected\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Defined how ATM signaling is terminated and pharmacologically overridden—caspase cleavage during apoptosis and direct caffeine inhibition both abolish kinase activity.\",\n      \"evidence\": \"In vitro caspase-3 cleavage and caffeine kinase-inhibition assays with in vivo Cds1/Chk2 readouts\",\n      \"pmids\": [\"10454555\", \"10531013\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Caffeine's selectivity over related PIKKs not fully defined\", \"Physiological role of apoptotic ATM cleavage uncertain\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Identified the Mre11 complex as the upstream damage sensor required for Tel1/ATM-dependent checkpoint activation, linking break detection to kinase output in mitotic and meiotic cells.\",\n      \"evidence\": \"Genetic epistasis, Rad53 phosphorylation, and Co-IP in S. cerevisiae\",\n      \"pmids\": [\"11430828\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which MRX activates the kinase not resolved\", \"Distinction between sensing and recruitment unclear\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Resolved the core activation switch—ATM is an inactive dimer whose intermolecular Ser1981 autophosphorylation drives monomerization and kinase activation, and showed activation responds to chromatin changes rather than direct DNA-end binding.\",\n      \"evidence\": \"Phosphospecific antibody, Co-IP, kinase assays, and S1981 mutagenesis in irradiated human cells; ChIP localization of Tel1 via Xrs2 C-terminus in yeast\",\n      \"pmids\": [\"12556884\", \"12923051\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How chromatin perturbation is transmitted to the dimer not defined\", \"S1981 autophosphorylation later shown insufficient as sole trigger in some systems\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Ordered ATM relative to ATR, showing ATM plus Mre11 nuclease processes DSBs into RPA-ssDNA to license ATR-Chk1 signaling in S/G2, establishing crosstalk between the two apical kinases.\",\n      \"evidence\": \"Epistasis with ATM inhibitor and Mre11 nuclease mutants, ChIP, Chk1 phosphorylation in cell-cycle-staged cells\",\n      \"pmids\": [\"16327781\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"CDK-dependence mechanism of resection not detailed\", \"Direct ATM substrates in the ATM-to-ATR handoff not enumerated\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Revealed telomere-specific regulation of Tel1/ATM, with Rif1/Rif2 attenuating kinase recruitment by competing for the Xrs2 C-terminus, integrating ATM activity into telomere length homeostasis.\",\n      \"evidence\": \"ChIP, yeast two-hybrid, and Rif2/Xrs2 competition binding assays in S. cerevisiae\",\n      \"pmids\": [\"19217405\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mammalian shelterin equivalence of Rif1/Rif2 competition not addressed here\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Expanded the ATM substrate repertoire into tumor-suppressor signaling by identifying RASSF1A Ser131 phosphorylation that engages the MST2/LATS1/p73 axis.\",\n      \"evidence\": \"In vivo phosphorylation, Ser131 mutagenesis, and downstream kinase/p73 stabilization assays\",\n      \"pmids\": [\"19962312\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab substrate assignment without reciprocal in vitro confirmation noted in narrative\", \"Quantitative contribution to checkpoint output unclear\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Showed that chromatin-modifying E3 ligases RNF8 and Chfr gate ATM activation through histone ubiquitination and H4K16 acetylation, connecting chromatin relaxation to kinase activation efficiency.\",\n      \"evidence\": \"RNF8/Chfr double-knockout mouse model with kinase activity and histone modification readouts\",\n      \"pmids\": [\"21706008\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct effect of chromatin relaxation on the ATM dimer not mechanistically traced\", \"Single lab\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Demonstrated that protein-bound or blocked DNA ends and Tel1-promoted MRX retention regulate the balance between end-processing and kinase activation, and that ATM feedback shapes end-tethering for repair.\",\n      \"evidence\": \"In vitro Tel1 kinase assays with Fab-tethered DNA, ChIP, and DSB repair/end-tethering assays in yeast\",\n      \"pmids\": [\"21402778\", \"26901759\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relationship between activation and resection in mammalian cells not directly tested\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Uncovered a DNA-damage-independent activation route—oxidative stress activates ATM via a distinct disulfide-crosslinked dimer requiring a specific cysteine, separating redox sensing from MRN-dependent break signaling.\",\n      \"evidence\": \"In vitro kinase reconstitution, non-reducing gels, and cysteine mutagenesis\",\n      \"pmids\": [\"20966255\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological redox triggers and downstream redox-specific substrates not fully mapped\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Defined how ATM pathway choice is encoded—NBS1 and ATMIN competitively bind ATM to route signaling to DSB versus chromatin-stress responses.\",\n      \"evidence\": \"Reciprocal Co-IP and NBS1/ATMIN single and double genetic deletions with substrate phosphorylation readouts\",\n      \"pmids\": [\"23219553\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of competitive binding to ATM not resolved\", \"Cofactor-specific substrate selectivity unclear\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Established a direct telomere-maintenance function—Tel1/ATM phosphorylates Ccq1 Thr93 to recruit telomerase, linking kinase activity to telomere elongation.\",\n      \"evidence\": \"In vitro kinase assay, T93A phosphosite mutagenesis, telomerase ChIP, telomere length analysis in fission yeast\",\n      \"pmids\": [\"22302936\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mammalian counterpart of Ccq1 phosphorylation not addressed\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identified non-DDR mitotic and chromatin-acetylation roles for ATM, including a Tankyrase1-NuMA1-BRCA1 spindle complex and KAT5/Tip60-mediated acetylation that activates ATM during S-phase formaldehyde damage independently of MRE11.\",\n      \"evidence\": \"Co-IP, phosphosite mutagenesis with spindle/PARylation readouts; KAT5 knockdown with ATM activation and acetylation assays\",\n      \"pmids\": [\"24553124\", \"26420831\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic link between acetylation and dimer dissociation not detailed\", \"Single-lab findings for each\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Revealed meiotic DSB interference as an ATM kinase function, with Tel1 suppressing adjacent break formation to space recombination events.\",\n      \"evidence\": \"Spo11-oligonucleotide mapping and kinase-dead tel1 analysis in yeast meiosis\",\n      \"pmids\": [\"25539084\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Substrate(s) mediating interference not identified\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Provided the structural basis of autoinhibition—cryo-EM and single-particle EM of the ATM/Tel1 homodimer showed FAT/kinase inter-subunit contacts and HEAT-repeat packing bury active sites and block substrate access.\",\n      \"evidence\": \"Cryo-EM of S. pombe Tel1 and single-particle EM of human ATM with mTOR-based fitting\",\n      \"pmids\": [\"27229179\", \"27097373\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Conformational transition to the active monomer not captured\", \"Resolution limits in human EM map\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Resolved the molecular requirements for MRX-dependent activation—an ATP-bound closed Mre11-Rad50 conformation, Rad50 ATPase activity, and long nucleosome-free DNA drive Tel1 activation independent of DNA termini, with nucleotide-bound Tel1 structures explaining substrate-access restriction.\",\n      \"evidence\": \"In vitro reconstitution with purified components, separation-of-function MR alleles, molecular dynamics, and cryo-EM of nucleotide-bound Tel1\",\n      \"pmids\": [\"31073030\", \"30698745\", \"31740029\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How the closed MR conformation allosterically opens the kinase not visualized\", \"Mammalian reconstitution not shown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Linked ufmylation to ATM activation—UFL1 recruited by MRN monoufmylates histone H4 to license Tip60/Suv39h1 recruitment, MRE11 K282 ufmylation supports MRN assembly, and ATM phosphorylation of UFL1 forms a positive feedback loop.\",\n      \"evidence\": \"Co-IP, ChIP, in vitro ufmylation, ATM kinase assays, and mutagenesis (MRE11 K282R, cancer-associated G285C)\",\n      \"pmids\": [\"30886146\", \"30783677\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Stoichiometry and kinetics of the feedback loop unclear\", \"Single-lab findings\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Extended ATM into iron metabolism and ferroptosis—ATM phosphorylates NCOA4 to sustain ferritinophagy and labile iron availability required for ferroptosis, largely independent of p53.\",\n      \"evidence\": \"Pharmacological inhibition, ATM/Trp53 CRISPR knockouts, ferritinophagy and iron assays, NCOA4 phosphorylation\",\n      \"pmids\": [\"36752571\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"NCOA4 phosphosite(s) not mapped\", \"Direct versus indirect phosphorylation not fully distinguished\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined a cytoplasmic, lysosomal role for ATM—association with dynein and phosphorylation of the lysosomal proton pump ATP6V1A regulate retrograde lysosomal transport, GLUT4 trafficking, and glucose uptake.\",\n      \"evidence\": \"Co-IP, ATP6V1A kinase assay, lysosomal fractionation, live imaging, glucose uptake in atm-null neurons\",\n      \"pmids\": [\"32757690\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How nuclear-damage-responsive ATM partitions to lysosomes unclear\", \"Single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how the distinct activation inputs (MRN/ATP-bound MR, oxidation, acetylation, ufmylation, cofactor competition) are mechanistically integrated into the conformational opening of the autoinhibited dimer, and how ATM substrate selectivity is encoded across its nuclear, telomeric, mitotic, and cytoplasmic functions.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structure of the activated ATM monomer bound to a physiological substrate\", \"Substrate-targeting rules for divergent pathways not defined\", \"Integration of redox and break-induced activation states unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 2, 9, 18, 20, 30, 32]},\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [22, 23, 15]},\n      {\"term_id\": \"GO:0140299\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [21, 29]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 8, 32]},\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [30]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [6, 35, 19]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [0, 2, 6, 22, 23, 32]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [2, 3, 5]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [7, 33, 9]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [1, 31]},\n      {\"term_id\": \"R-HSA-1474165\", \"supporting_discovery_ids\": [19, 35]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [10, 12, 31]}\n    ],\n    \"complexes\": [\"MRN/MRX complex (associated activator)\", \"ATM-Tankyrase1-NuMA1-BRCA1 mitotic complex\"],\n    \"partners\": [\"NBS1\", \"ATMIN\", \"MRE11\", \"RAD50\", \"FOXO3a\", \"KAT5\", \"UFL1\", \"BRCA1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}