Affinage

ATM

Serine-protein kinase ATM · UniProt Q13315

Length
3056 aa
Mass
350.7 kDa
Annotated
2026-06-09
100 papers in source corpus 36 papers cited in narrative 36 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 20 steps
  1. 1996 High

    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

    PMID:8553072

    Open questions at the time
    • Did not resolve the direct substrate of Tel1 versus Mec1
    • Mammalian ATM substrate identity not established here
  2. 1997 Medium

    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

    PMID:9398850

    Open questions at the time
    • Co-localization does not establish direct phosphorylation of RPA or recombination factors
    • Functional consequence at recombination sites not dissected
  3. 1999 High

    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

    PMID:10454555 PMID:10531013

    Open questions at the time
    • Caffeine's selectivity over related PIKKs not fully defined
    • Physiological role of apoptotic ATM cleavage uncertain
  4. 2001 High

    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

    PMID:11430828

    Open questions at the time
    • Mechanism by which MRX activates the kinase not resolved
    • Distinction between sensing and recruitment unclear
  5. 2003 High

    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

    PMID:12556884 PMID:12923051

    Open questions at the time
    • How chromatin perturbation is transmitted to the dimer not defined
    • S1981 autophosphorylation later shown insufficient as sole trigger in some systems
  6. 2005 High

    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

    PMID:16327781

    Open questions at the time
    • CDK-dependence mechanism of resection not detailed
    • Direct ATM substrates in the ATM-to-ATR handoff not enumerated
  7. 2009 High

    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

    PMID:19217405

    Open questions at the time
    • Mammalian shelterin equivalence of Rif1/Rif2 competition not addressed here
  8. 2009 Medium

    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

    PMID:19962312

    Open questions at the time
    • Single-lab substrate assignment without reciprocal in vitro confirmation noted in narrative
    • Quantitative contribution to checkpoint output unclear
  9. 2011 Medium

    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

    PMID:21706008

    Open questions at the time
    • Direct effect of chromatin relaxation on the ATM dimer not mechanistically traced
    • Single lab
  10. 2011 High

    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

    PMID:21402778 PMID:26901759

    Open questions at the time
    • Relationship between activation and resection in mammalian cells not directly tested
  11. 2010 High

    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

    PMID:20966255

    Open questions at the time
    • Physiological redox triggers and downstream redox-specific substrates not fully mapped
  12. 2012 High

    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

    PMID:23219553

    Open questions at the time
    • Structural basis of competitive binding to ATM not resolved
    • Cofactor-specific substrate selectivity unclear
  13. 2012 High

    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

    PMID:22302936

    Open questions at the time
    • Mammalian counterpart of Ccq1 phosphorylation not addressed
  14. 2015 Medium

    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

    PMID:24553124 PMID:26420831

    Open questions at the time
    • Mechanistic link between acetylation and dimer dissociation not detailed
    • Single-lab findings for each
  15. 2015 High

    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

    PMID:25539084

    Open questions at the time
    • Substrate(s) mediating interference not identified
  16. 2016 High

    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

    PMID:27097373 PMID:27229179

    Open questions at the time
    • Conformational transition to the active monomer not captured
    • Resolution limits in human EM map
  17. 2019 High

    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

    PMID:30698745 PMID:31073030 PMID:31740029

    Open questions at the time
    • How the closed MR conformation allosterically opens the kinase not visualized
    • Mammalian reconstitution not shown
  18. 2019 Medium

    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)

    PMID:30783677 PMID:30886146

    Open questions at the time
    • Stoichiometry and kinetics of the feedback loop unclear
    • Single-lab findings
  19. 2019 Medium

    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

    PMID:36752571

    Open questions at the time
    • NCOA4 phosphosite(s) not mapped
    • Direct versus indirect phosphorylation not fully distinguished
  20. 2020 Medium

    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

    PMID:32757690

    Open questions at the time
    • How nuclear-damage-responsive ATM partitions to lysosomes unclear
    • Single lab

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 7 GO:0140657 ATP-dependent activity 3 GO:0098772 molecular function regulator activity 2 GO:0140299 molecular sensor activity 1
Localization
GO:0000228 nuclear chromosome 3 GO:0005634 nucleus 3 GO:0005764 lysosome 1
Pathway
R-HSA-73894 DNA Repair 6 R-HSA-1640170 Cell Cycle 3 R-HSA-4839726 Chromatin organization 3 R-HSA-5357801 Programmed Cell Death 3 R-HSA-1474165 Reproduction 2 R-HSA-8953897 Cellular responses to stimuli 2
Partners
ATMINBRCA1FOXO3AKAT5MRE11NBS1RAD50UFL1
Complex memberships
ATM-Tankyrase1-NuMA1-BRCA1 mitotic complexMRN/MRX complex (associated activator)

Evidence

Reading pass · 36 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2003 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. Phosphospecific antibody detection, immunoprecipitation, kinase activity assays, irradiation with defined doses Nature High 12556884
2010 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. In vitro kinase assay, non-reducing gel electrophoresis, cysteine mutagenesis, cell-based activation assays Science High 20966255
2005 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. Epistasis analysis with ATM inhibitor and Mre11 nuclease mutants, ChIP, immunofluorescence, flow cytometry, Chk1 phosphorylation assay Nature Cell Biology High 16327781
1996 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. Genetic suppressor screen, phosphorylation assays, overexpression studies in yeast Science High 8553072
2001 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. Genetic epistasis, Rad53 phosphorylation assays, co-immunoprecipitation, meiotic and mitotic checkpoint analysis in yeast Molecular Cell High 11430828
1999 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. In vitro ATM kinase assay with caffeine, in vivo Cds1 phosphorylation assay Current Biology High 10531013
2003 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. ChIP of Tel1 at DSBs, C-terminal truncation of Xrs2, Rad53 phosphorylation assays Genes & Development High 12923051
1999 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. In vitro caspase cleavage assays, in vivo apoptosis induction with multiple stimuli, ATM kinase assay, DNA-binding assay Molecular and Cellular Biology High 10454555
2008 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. Co-immunoprecipitation, FOXO3a knockdown/overexpression, immunofluorescence for ATM-pS1981 and γH2AX foci, cell cycle checkpoint assays Nature Cell Biology Medium 18344987
2019 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. Pharmacological ATM inhibition, genetic ATM/Trp53 knockout (CRISPR), ferritinophagy assays, iron measurement, phosphorylation assays for NCOA4 Autophagy Medium 36752571
2019 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. Co-immunoprecipitation, ChIP, in vitro ufmylation assay, ATM kinase assay, knockdown experiments Nature Communications Medium 30886146
2019 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. Site-directed mutagenesis, Co-immunoprecipitation, ATM activation assays (pS1981), homologous recombination assays Nucleic Acids Research Medium 30783677
2011 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. Double-knockout mouse model, immunofluorescence, kinase activity assays, histone modification analysis, in vivo tumor development Nature Structural & Molecular Biology Medium 21706008
2016 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. Cryo-EM single-particle reconstruction of full-length ATM/Tel1 Nature Communications High 27229179
2016 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. Single-particle electron microscopy, structural fitting with mTOR crystal structure Cell Cycle Medium 27097373
2019 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. Cryo-EM structure determination of nucleotide-bound Tel1 Structure High 31740029
2009 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. ChIP at telomeres, yeast two-hybrid, genetic epistasis, Rif2/Xrs2 binding competition assays Molecular Cell High 19217405
2008 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. Co-immunoprecipitation, ChIP at DSBs, genetic analysis, computational structural analysis Genes & Development Medium 18334620
2012 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. In vitro kinase assay with purified Tel1/Rad3, phosphosite mutagenesis (T93A), telomerase ChIP, telomere length analysis Genes & Development High 22302936
2015 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. Spo11-oligonucleotide mapping, kinase-dead tel1 mutation analysis, genetic epistasis in yeast meiosis Nature High 25539084
2009 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. In vivo phosphorylation assay, site-directed mutagenesis of Ser131, kinase activity assays for MST2/LATS1, p73 stabilization assay Current Biology Medium 19962312
2012 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. Co-immunoprecipitation, genetic deletion (atmin and nbs1 mutant cells), ATM substrate phosphorylation assays, radiosensitivity assays Cell Reports High 23219553
2019 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. In vitro Tel1 kinase reconstitution with purified components, ATPase-dead Rad50 mutants, varying DNA substrates, physical binding assays Journal of Biological Chemistry High 31073030
2019 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. Separation-of-function mutant analysis, ChIP for Tel1 at DSBs, Tel1 kinase assays, molecular dynamics simulations, Co-immunoprecipitation Nucleic Acids Research High 30698745
2011 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. ChIP, synthetic phenotype screen, DSB repair assays (HR and NHEJ), end-tethering assays, genetic epistasis PLoS Biology Medium 26901759
2011 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. ChIP, telomere resection assays, telomere length analysis, gain-of-function tel1-hy909 mutant Molecular and Cellular Biology Medium 22354991
2013 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. ChIP, ssDNA accumulation assays, Rad53 phosphorylation, genetic analysis of mec1 and rad9 mutants EMBO Journal Medium 24357557
2011 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. In vitro Tel1 kinase assay with Fab-tethered DNA ends, in vivo phosphorylation assays in sae2Δ and mre11-3 mutants Molecular and Cellular Biology High 21402778
2015 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. Co-immunoprecipitation, immunofluorescence, mutagenesis of ATM phosphorylation sites in NuMA1, PARylation assay Cell Cycle Medium 24553124
2015 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. Co-immunoprecipitation, ubiquitination assays, ATM knockdown/inhibition, in vitro and in vivo tumorigenicity assays Nature Communications Medium 25881002
2020 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. Co-immunoprecipitation of ATM with dynein, ATM kinase assay for ATP6V1A, lysosomal fractionation, live-cell imaging, glucose uptake assay in atm-null neurons Autophagy Medium 32757690
2015 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. KAT5 inhibition/knockdown, ATM activation assays (pS1981), acetylation assays, intra-S-phase checkpoint assay, MRE11 inhibition Nucleic Acids Research Medium 26420831
2015 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. In vitro ATM kinase assay, Co-immunoprecipitation, laser microirradiation/recruitment assay, GIT2 knockout mice, BRCA1 stabilization assay Molecular and Cellular Biology Medium 25605334
2000 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. Genetic epistasis with Atm-/-, p53-/-, and Bax-/- mouse models, TUNEL assay for apoptosis after irradiation Apoptosis High 11303911
2007 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. CFP-YFP FRET biosensor in living cells, ATM/ATR/DNA-PK specificity testing DNA Repair Medium 17428747
1997 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. Immunolocalization on meiotic chromosome spreads from Atm-/- and wild-type mice, co-localization analysis Nature Genetics Medium 9398850

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2003 DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation. Nature 2671 12556884
2010 ATM activation by oxidative stress. Science (New York, N.Y.) 901 20966255
2005 ATM- and cell cycle-dependent regulation of ATR in response to DNA double-strand breaks. Nature cell biology 870 16327781
2000 The many substrates and functions of ATM. Nature reviews. Molecular cell biology 631 11252893
1996 Regulation of RAD53 by the ATM-like kinases MEC1 and TEL1 in yeast cell cycle checkpoint pathways. Science (New York, N.Y.) 545 8553072
2014 ATM and ATR as therapeutic targets in cancer. Pharmacology & therapeutics 509 25512053
2001 ATM and ATR: networking cellular responses to DNA damage. Current opinion in genetics & development 509 11163154
2016 ATM Mutations in Cancer: Therapeutic Implications. Molecular cancer therapeutics 385 27413114
2015 Mechanisms of ATM Activation. Annual review of biochemistry 382 25580527
2004 DNA damage-induced activation of ATM and ATM-dependent signaling pathways. DNA repair 362 15279774
2001 A DNA damage response pathway controlled by Tel1 and the Mre11 complex. Molecular cell 336 11430828
2007 ATM activation and DNA damage response. Cell cycle (Georgetown, Tex.) 320 17457059
1998 ATM: from gene to function. Human molecular genetics 270 9735376
2004 ATM and ataxia telangiectasia. EMBO reports 269 15289825
1999 Caffeine inhibits the checkpoint kinase ATM. Current biology : CB 250 10531013
2003 ATM-related Tel1 associates with double-strand breaks through an Xrs2-dependent mechanism. Genes & development 231 12923051
1999 ATM: a mediator of multiple responses to genotoxic stress. Oncogene 224 10557105
2001 ATM, a central controller of cellular responses to DNA damage. Cell death and differentiation 197 11687884
2023 ATM orchestrates ferritinophagy and ferroptosis by phosphorylating NCOA4. Autophagy 195 36752571
2015 ATM and ATR signaling at a glance. Journal of cell science 194 26567218
2019 ATM in DNA repair in cancer. Pharmacology & therapeutics 193 31299316
2000 The Mre11 complex and ATM: collaborating to navigate S phase. Current opinion in cell biology 181 10801460
2013 ATM signalling and cancer. Oncogene 179 23851492
2011 ATM and the molecular pathogenesis of ataxia telangiectasia. Annual review of pathology 175 22035194
2008 Functional interaction between FOXO3a and ATM regulates DNA damage response. Nature cell biology 169 18344987
2019 UFL1 promotes histone H4 ufmylation and ATM activation. Nature communications 154 30886146
2007 ATM and ATR: components of an integrated circuit. Cell cycle (Georgetown, Tex.) 152 17312392
2007 ATM prevents the persistence and propagation of chromosome breaks in lymphocytes. Cell 152 17599403
2013 Pathogenesis of ataxia-telangiectasia: the next generation of ATM functions. Blood 150 23440242
2002 ATM function and telomere stability. Oncogene 148 11850786
2006 ATM and breast cancer susceptibility. Oncogene 145 16998505
2019 MRE11 UFMylation promotes ATM activation. Nucleic acids research 138 30783677
2015 Tel1(ATM)-mediated interference suppresses clustered meiotic double-strand-break formation. Nature 121 25539084
1997 ATM and RPA in meiotic chromosome synapsis and recombination. Nature genetics 121 9398850
1996 ATM mutations in cancer families. Cancer research 106 8797579
2009 Rif1 and rif2 inhibit localization of tel1 to DNA ends. Molecular cell 104 19217405
2005 Induction and utilization of an ATM signaling pathway by polyomavirus. Journal of virology 101 16189003
1999 Cleavage and inactivation of ATM during apoptosis. Molecular and cellular biology 95 10454555
2021 ATM's Role in the Repair of DNA Double-Strand Breaks. Genes 93 34573351
2011 ATM protein kinase: the linchpin of cellular defenses to stress. Cellular and molecular life sciences : CMLS 92 21533982
2009 ATM regulates a RASSF1A-dependent DNA damage response. Current biology : CB 92 19962312
2004 ATM gene and lymphoid malignancies. Leukemia 91 14628072
2004 ATM is required for telomere maintenance and chromosome stability during Drosophila development. Current biology : CB 91 15296750
2011 Chfr and RNF8 synergistically regulate ATM activation. Nature structural & molecular biology 87 21706008
2004 ATM and ATR: sensing DNA damage. World journal of gastroenterology 87 14716813
2013 Interplays between ATM/Tel1 and ATR/Mec1 in sensing and signaling DNA double-strand breaks. DNA repair 83 23953933
2007 Tel1 kinase and subtelomere-bound Tbf1 mediate preferential elongation of short telomeres by telomerase in yeast. EMBO reports 82 17917674
2005 ATM signaling and 53BP1. Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology 81 16024119
2002 ATM mutations in sporadic lymphoid tumours. Leukemia & lymphoma 70 12400598
2011 Pch2 acts through Xrs2 and Tel1/ATM to modulate interhomolog bias and checkpoint function during meiosis. PLoS genetics 65 22072981
2008 The ATM gene and ataxia telangiectasia. Anticancer research 63 18383876
2018 Ataxia-telangiectasia gene (ATM) mutation heterozygosity in breast cancer: a narrative review. Current oncology (Toronto, Ont.) 60 29719442
2012 Tel1(ATM) and Rad3(ATR) phosphorylate the telomere protein Ccq1 to recruit telomerase and elongate telomeres in fission yeast. Genes & development 60 22302936
2023 Targeting ATM and ATR for cancer therapeutics: Inhibitors in clinic. Drug discovery today 58 37302542
2016 Numerical and spatial patterning of yeast meiotic DNA breaks by Tel1. Genome research 58 27923845
2004 Recombination and the Tel1 and Mec1 checkpoints differentially effect genome rearrangements driven by telomere dysfunction in yeast. Nature genetics 58 15133512
2013 Mec1/ATR regulates the generation of single-stranded DNA that attenuates Tel1/ATM signaling at DNA ends. The EMBO journal 57 24357557
2022 ATM: Functions of ATM Kinase and Its Relevance to Hereditary Tumors. International journal of molecular sciences 54 35008949
2015 ATM kinase sustains HER2 tumorigenicity in breast cancer. Nature communications 54 25881002
2020 ATM loss disrupts the autophagy-lysosomal pathway. Autophagy 53 32757690
2016 Structure of the intact ATM/Tel1 kinase. Nature communications 52 27229179
2003 Replication checkpoint protein Mrc1 is regulated by Rad3 and Tel1 in fission yeast. Molecular and cellular biology 50 14585996
2015 Sae2 Function at DNA Double-Strand Breaks Is Bypassed by Dampening Tel1 or Rad53 Activity. PLoS genetics 49 26584331
2014 The versatile functions of ATM kinase. Biomedical journal 49 24667671
2007 The NBS1-ATM connection revisited. Cell cycle (Georgetown, Tex.) 48 17881893
2001 ATM as a target for novel radiosensitizers. Seminars in radiation oncology 46 11677656
2016 Structure of the human dimeric ATM kinase. Cell cycle (Georgetown, Tex.) 44 27097373
2008 Tel2 mediates activation and localization of ATM/Tel1 kinase to a double-strand break. Genes & development 44 18334620
2003 The ATM-related Tel1 protein of Saccharomyces cerevisiae controls a checkpoint response following phleomycin treatment. Nucleic acids research 44 12626713
2016 Tel1 and Rif2 Regulate MRX Functions in End-Tethering and Repair of DNA Double-Strand Breaks. PLoS biology 43 26901759
2000 ATM dependent apoptosis in the nervous system. Apoptosis : an international journal on programmed cell death 42 11303911
2012 A balance between Tel1 and Rif2 activities regulates nucleolytic processing and elongation at telomeres. Molecular and cellular biology 40 22354991
2016 ATM protein is deficient in over 40% of lung adenocarcinomas. Oncotarget 39 27259260
2015 Reduced Crossover Interference and Increased ZMM-Independent Recombination in the Absence of Tel1/ATM. PLoS genetics 39 26305689
2012 Competition between NBS1 and ATMIN controls ATM signaling pathway choice. Cell reports 38 23219553
2020 Clinical potential of ATM inhibitors. Mutation research 36 32304909
2019 Cryo-EM Structure of Nucleotide-Bound Tel1ATM Unravels the Molecular Basis of Inhibition and Structural Rationale for Disease-Associated Mutations. Structure (London, England : 1993) 36 31740029
2011 ATM regulates a DNA damage response posttranscriptional RNA operon in lymphocytes. Blood 36 21209379
2007 Monitoring ATM kinase activity in living cells. DNA repair 36 17428747
2019 The ATP-bound conformation of the Mre11-Rad50 complex is essential for Tel1/ATM activation. Nucleic acids research 35 30698745
2017 Ataxia telangiectasia syndrome: moonlighting ATM. Expert review of clinical immunology 32 29034753
2014 ATM activation in hypoxia - causes and consequences. Molecular & cellular oncology 32 27308313
2001 Hyperactivation of the yeast DNA damage checkpoint by TEL1 and DDC2 overexpression. The EMBO journal 32 11707419
2019 Activation of Tel1ATM kinase requires Rad50 ATPase and long nucleosome-free DNA but no DNA ends. The Journal of biological chemistry 31 31073030
2024 ATM inhibition exploits checkpoint defects and ATM-dependent double strand break repair in TP53-mutant glioblastoma. Nature communications 30 38906885
2018 Management of Anaplastic Thyroid Carcinoma: the Fruits from the ATC Research Consortium of Japan. Journal of Nippon Medical School = Nippon Ika Daigaku zasshi 30 29540641
2015 Nuclear GIT2 is an ATM substrate and promotes DNA repair. Molecular and cellular biology 30 25605334
2014 ATM controls proper mitotic spindle structure. Cell cycle (Georgetown, Tex.) 30 24553124
2009 ATM- and ATR-mediated response to DNA damage induced by a novel camptothecin, ST1968. Cancer letters 30 20042274
2019 ATM deficiency promotes progression of CRPC by enhancing Warburg effect. Endocrine-related cancer 29 30400006
2015 ATM and KAT5 safeguard replicating chromatin against formaldehyde damage. Nucleic acids research 28 26420831
2021 ATM Kinase Dead: From Ataxia Telangiectasia Syndrome to Cancer. Cancers 27 34771661
2017 Taming Tricky DSBs: ATM on duty. DNA repair 27 28624372
2010 Ataxia-telangiectasia mutated kinase (ATM) as a central regulator of radiation-induced DNA damage response. Acta medica (Hradec Kralove) 27 20608227
2008 High rates of "unselected" aneuploidy and chromosome rearrangements in tel1 mec1 haploid yeast strains. Genetics 27 18458104
2008 ATMINistrating ATM signalling: regulation of ATM by ATMIN. Cell cycle (Georgetown, Tex.) 27 19001856
2019 KAT5 promotes invasion and metastasis through C-MYC stabilization in ATC. Endocrine-related cancer 26 30400007
2014 Multifunctional role of ATM/Tel1 kinase in genome stability: from the DNA damage response to telomere maintenance. BioMed research international 26 25247188
2011 Activation of protein kinase Tel1 through recognition of protein-bound DNA ends. Molecular and cellular biology 26 21402778
2007 Dominant TEL1-hy mutations compensate for Mec1 lack of functions in the DNA damage response. Molecular and cellular biology 26 17954565

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