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FLASH GENE
Symbol ATM contributors: mct/ - updated : 31-01-2015
HGNC name ataxia telangiectasia mutated
HGNC id 795
Corresponding disease
ATM ataxia-telangiectasia
MTCL mantle cell lymphoma
Location 11q22.3      Physical location : 108.093.558 - 108.239.826
Synonym name
  • ataxia telangiectasia mutated (includes complementation groups A, C and D)
  • TEL1, telomere maintenance 1, homolog (S. cerevisiae)
  • human phosphatidylinositol 3-kinase homolog
  • AT mutated
  • TEL1, telomere maintenance 1, homolog
  • serine-protein kinase ATM
  • Synonym symbol(s) D11S2052, ATA, ATC, ATD, AT1, ATE, ATDC, TEL1, TEL1p, TELO1, ATD, DKFZp781A0353, MGC74674
    EC.number 2.7.11.1
    DNA
    TYPE functioning gene
    STRUCTURE 146.27 kb     63 Exon(s)
    10 Kb 5' upstream gene genomic sequence study
    MAPPING cloned Y linked N status confirmed
    Physical map
    CASP4 11q22.2-q22.3 caspase 4, apoptosis-related cysteine protease CASP5 11q22.2-q22.3 caspase 5, apoptosis-related cysteine protease CASP1 11q22.2-q22.3 caspase 1, apoptosis-related cysteine protease (interleukin 1, beta, convertase) COP  clathrin-ordered protein ICEBERG 11q21-q22 ICEBERG caspase-1 inhibitor OR2AL1P 11q23.3 olfactory receptor, family 2, subfamily AL, member 1 pseudogene GRIA4 11q22.3 glutamate receptor, ionotrophic, AMPA 4 KIAA1826 11q22 KIAA1826 protein KBTBD3 11q22.3 kelch repeat and BTB (POZ) domain containing 3 AASDHPPT 11q22 aminoadipate-semialdehyde dehydrogenase-phosphopantetheinyl transferase GUCY1A2 11q21-q22 guanylate cyclase 1, soluble, alpha 2 LOC341230 11q23.1 similar to argininosuccinate synthetase FLJ32343 11q23.1 hypothetical protein FLJ32343 LOC91801 11q23.1 hypothetical protein BC015183 DKFZp547C176 11q23.1 hypothetical protein DKFZp547C176 SLN 11q22-q23 sarcolipin LOC203930 11q23.1 sorting nexin 7 pseudogene SLC35F2 11q23.1 solute carrier family 35, member F2 RAB39 11q22-q23 RAB39, member RAS oncogene family CUL5 11q22-q23 cullin 5 ACAT1 11q22.3 acetyl-Coenzyme A acetyltransferase 1 (acetoacetyl Coenzyme A thiolase) NPAT 11q22-q23 nuclear protein, ataxia-telangiectasia locus ATM 11q22.3 ataxia telangiectasia mutated (includes complementation groups A, C and D) MGC33948 11q23.1 hypothetical protein MGC33948 MGC33424 11q23.1 hypothetical protein MGC33424 SLAC2-B 11q23.1 hypothetical protein MGC33424 DDX10 11q22-q23 DEAD (Asp-Glu-Ala-Asp) box polypeptide 10 HCP29 11q22.3 cytochrome c, somatic pseudogene LOC260340 11q23.1 processed pseudogene mtTFA 2 LOC390249 11 similar to 40S ribosomal protein SA (P40) (34/67 kDa laminin receptor) (Colon carcinoma laminin-binding protein) (NEM/1CHD4) (Multidrug resistance-associated protein MGr1-Ag) LOC390250 11 similar to RPB5_Human KIAA1726 11q23.1 KIAA1726 protein RDX 11q22.3-q23.1 radixin FDX1 11q22.3-q23.1 ferredoxin 1 ARHGAP20 11q23.2 Rho GTPase activating protein 20 LOC120364 11q23.2 similar to Hnrpa1 protein MGC50104 11q23.2 Similar to RIKEN cDNA 1810046K07 gene LOC120376 11q23.2 hypothetical protein LOC120376 POU2AF1 11q23.1 POU domain, class 2, associating factor 1 BTG4 11q23.2-q23.3 B-cell translocation gene 4
    regionally located in a region of reduced recombination and extensive linkage disequilibrium
    RNA
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    63 splicing 13147 350.6 3056 - 1997 9108147
    EXPRESSION
    Type widely
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    blood / hematopoieticthymus    
    Digestiveintestinelarge intestinecolon  
     intestinesmall intestine  highly
    Endocrineadrenal gland   highly
     parathyroid   highly
    Lymphoid/Immunelymph node   highly
    Nervousbrainhindbraincerebellum highly
    Respiratorylung    
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Epithelialsecretoryglandularendocrine 
    Muscularstriatumskeletal  
    cells
    SystemCellPubmedSpeciesStageRna symbol
    Blood/Hematopoieticleukocyte
    NervousPurkinje cell
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    physiological period pregnancy
    Text placenta
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • a leucine zipper
  • a proline-rich region binding to the SH3 domain of CABL
  • a domain of homology with PI3 kinase (C terminal) associating with TP53
  • C-terminus encompassing the kinase domain (&
  • 8764;26802960), the PIKK-regulatory domain (&
    8764;29603025), and the FATC domain (&
    8764;30253056) and mediating interaction wih PCNA
    mono polymer monomer , tetramer
    HOMOLOGY
    interspecies homolog to yeast S.cerevisiae ESR1/MEC1cell cycle G2 checkpoint gene
    homolog to yeast S.pombe RAD3
    homolog to Drosophila mei-41
    homolog to yeast TOR,TOR2
    homolog to murine Atm
    intraspecies homolog to TEL1
    Homologene
    FAMILY
  • phosphoinositide 3-kinase (PI3-kinase)-related protein kinase (PIKK) family
  • ATM subfamily
  • CATEGORY enzyme , signaling , receptor membrane serine/threonine
    SUBCELLULAR LOCALIZATION     intracellular
    intracellular,cytoplasm,cytosolic,vesicle
    intracellular,nucleus,nucleoplasm
    intracellular,nucleus,chromatin/chromosome
    intracellular,nucleus,nucleolus
    text
  • in endocytic vesicles in association with beta-adaptin
  • nuclear matrix
  • localized to the cytoplasm of Purkinje neurons
  • basic FUNCTION
  • required in the regulation of mitochondrial function
  • activating TP53 by phosphorylation in association with 14.3.3 proteins YWHA*
  • essential regulator of stress response and reactive oxygen species-induced DNA damage that is critical for hematopoietic stem cell self-renewal
  • activating ABL1 (cABL) and TP73 in a mismatch repair dependent apoptosis pathway
  • involved in cellular responses to ionizing radiation (IR)-induced DNA damage such as double strand breaks and cell cycle control through phosphorylation of BRCA1
  • leading to cell cycle arrest and apoptosis
  • playing a role in the repair of oxidative damage to telomeric DNA and for maintaining telomeric integrity
  • playing a role in gonad and neurological functions
  • playing an important role in the prevention of both T and B cell malignancies
  • regulating TP53 stability and neuronal death, independently of CHK2 in response to DNA damage
  • promoting apoptosis and suppressing tumorigenesis in response to MYC overexpression (ATM-dependent response to this damage is critical for TP53 activation, apoptosis, and the suppression of tumor development)
  • exhibiting selective substrate specificity in response to different genotoxic agents
  • functioning directly in the repair of chromosomal DNA DSBs by maintaining DNA ends in repair complexes generated during lymphocyte antigen receptor gene assembly
  • have postreplication repair functions distinct from those of H2AX, but likely have independent functions that theoretically could synergize in DNA repair and maintenance of genomic integrity
  • ATM family checkpoint kinase, playing an important role in telomere elongation (preferentially associates with the shortest telomeres and stimulates their elongation by telomerase)
  • with ATR control mitotic events in vertebrate cells by targeting CEP63 and centrosome dependent spindle assembly
  • insulin-responsive protein and a major upstream activator of AKT following insulin treatment
  • potentially involved in the development of insulin resistance through down-regulation of AKT activity
  • with ATR are required for recovery from replication-dependent DSBs and to regulate RAD51 foci formation
  • essential for IL6 secretion during oncogene-induced senescence and by damaged cells that bypass senescence)
  • ATM and TP53-associated ZNF420 are negative regulator of TP53-mediated apoptosis
  • controls stability and pro-apoptotic function of DYRK2 in response to DNA damage
  • essential role for ATM in the intracellular control of DYRK2
  • prevents RNA polymerase II elongation-dependent chromatin decondensation at regions distal to DNA double-strand breaks
  • regulate oxidative stress-induced endothelial cell dysfunction and premature senescence
  • through an ATM/AKT1/TP53/CDKN1A-dependent signaling pathway mediates an instructive role in oxidative stress-induced endothelial dysfunction and premature senescence
  • ATM has a critical regulatory function in controlling DNA end-stability and error-prone DSB repair and MRE11A nuclease plays a major role in initiating microhomology-mediated end joining in cells, particularly in neuronal cells, which are post-mitotic
  • sensor of oxidative stress that activates compensatory signaling (including mitochondrial biogenesis) in response to ROS
  • required with ATR for accurate response to replication arrest crucial to preserve genome stability
  • important sensor of reactive oxygen species in human cells
  • may similarly regulate global cellular responses to oxidative stress
  • important to limit incorrect end utilization during classical non-homologous end joining (
  • NHEJ1, ATM and H2AFX all have fundamental roles in processing and joining DNA ends during V(D)J recombination, but these roles have been masked by unanticipated functional redundancies
  • protects cells from ROS accumulation by stimulating NADPH production and promoting the synthesis of nucleotides required for the repair of DSBs (double strand breaks)
  • in the context of excessive DNA damage, ATM employs IKBKG and RIPK1 through autocrine TNF signaling to switch on cytokine production and caspase activation
  • phosphorylates MDC1 at Thr-98 following DNA damage, which promotes its oligomerization
  • sensor of cellular DNA damage, playing potentially through ATM-signaling pathway a role in regulating L1 retrotransposition
  • has a role in L1 retrotransposition in neuronal and nonneuronal cell types
  • dysfunctional telomeres promote ATM/ATR-dependent degradation of CDC25C phosphatase to block mitotic entry, thereby preventing telomere dysfunction-driven genomic instability
  • is functional near telomeres and is involved in end protection at telomeric double-strand breaks (DSBs), but is not required for the extensive resection at telomeric DSBs
  • ATM-mediated phosphorylation has a role in the response to multiple types of genotoxic stress
  • NBN and ATM are key factors for DNA Double Strand Break (DSB) signaling and repair
  • NBN and ATM collaborate to prevent DSB accumulation and apoptosis during development in a tissue- and developmental stage-specific manner
  • is needed not only for the initiation but also for the completion of HR
  • CELLULAR PROCESS cell cycle, checkpoint
    cell life, cell death/apoptosis
    nucleotide, repair
    nucleotide, genomic integrity
    PHYSIOLOGICAL PROCESS development , nervous system , reproduction/sex
    text
  • G1/S checkpoint
  • T-cell development
  • vesicle and/or protein transport
  • PATHWAY
    metabolism
    signaling signal transduction
    chromosome instability pathway
    a component
  • part of MRE11A-ATM-RNF168 signaling complex, implicated in a signaling cascade that directly promotes a PI3K-independent pathway of AKT1 phosphorylation
  • INTERACTION
    DNA binding to telomeres
    RNA
    small molecule
    protein
  • FANCD2 (for regulating discrete cellular signaling pathway)
  • beta adaptin for the axonal transport and vesicle trafficking in the central nervous system, TP53, nibrin, BRCA1, RAD9, ABL1
  • preferentially associated with the shortest telomeres and stimulating their elongation by telomerase
  • interacting with TTC5 (phosphorylating TTC5)(Adams 2008)
  • cooperates with both NBS1 and H2AFX for regulation of ATM-dependent cell cycle checkpoint in response to DNA damage
  • phosphorylating DYRK2 (ATM-mediated phosphorylation of Ser-369 is crucial for DYRK2 activation in response to DNA damage)
  • binds to the MRN (MRE11, RAD50, NBN) heterotrimer at sites of double-strand breaks
  • interacts with the DNA repair enzyme Artemis specifically in G2 to promote DNA repair
  • PNKP is an ATM target (ATM-mediated phosphorylation of PNKP is required for effective DNA double-strand break repair)
  • activated by double-strand DNA breaks and subsequently phosphorylates downstream substrates, such as CHEK2, TP53, BRCA1, and the MRN complex
  • ATM bind two regions in PCNA (stimulate DNA polymerase activity in a PCNA-dependent manner)
  • SKP2-mediatetd NBN ubiquitination is a vital event for ATM activation in response to DNA damage
  • CCAR2 phosphorylation by ATM/ATR inhibits SIRT1 deacetylase in response to DNA damage
  • BRCA1/E2F1/RBBP8 binding to ATM promoter activates ATM transcription
  • TCL1A and ATM functionally cooperate to modulate similar apoptosis-related cellular pathways
  • phosphorylation of NBN regulates its accumulation, and that of ATM, at sites of DNA DSB as well as the timing of the repair of these sites
  • role for ATM as a suppressor of SATB1-induced malignancy in breast epithelial cells
  • NBN plays unique and essential roles in ATM activation in response to DNA double-strand breaks
  • phosphorylation of DAXX by ATM upon DNA damage disrupts the DAXX-MDM2 interaction and facilitates TP53 activation)
  • binds to the N-terminal region of ATM, accelerates ATM activation
  • ATM is needed for later steps in HR after RAD51 nucleofilament formation
  • cell & other
    REGULATION
    induced by ionizing radiation
    inhibited by wortmannin, caffeine and LY294002
    Other may be regulated directly by FOXO3 in the DNA-damage response
    ASSOCIATED DISORDERS
    corresponding disease(s) ATM , MTCL
    related resource Ataxia-Telangiectasia
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    tumoral somatic mutation deletion    
    in B cell chronic lymphocytic leukemia
    constitutional germinal mutation      
    in ataxia telangiectasia (see AT) but not mutated in childhood T-ALL
    tumoral   deletion    
    in mantle cell lymphoma (see also MTCL and TSG11F) and in lymphoblastic leukemia with favorable prognosis, in T-cell lymphomas with aberrant recombination between GZMB and GZMH
    constitutional   deletion    
    a 4nt deletion involved in the splicing processing defect in ATM
    tumoral       loss of function
    in T cell prolymphocytic leukaemia (T-PLL), B-cell chronic lymphocytic leukaemia (B-CLL) and mantle cell lymphoma (MCL)
    tumoral     --low  
    in T-cell prolymphocytic leukemia
    tumoral     --over  
    in lung carcinoma, in esophageal squamous cell carcinoma and its premalignant lesions when compared with normal tissues and increased ATM expression was associated with tobacco smoke exposure and tumor de-differentiation
    constitutional       loss of function
    acute effect of ATM inhibition on COX activity in skeletal muscle, it is likely that chronic ATM deficiency results in additional mitochondrial deficits in other tissue or cell types
    Susceptibility
  • breast cancer susceptibility in AT heterozygotes
  • hereditary non polyposis colorectal cancer (HNPCC)
  • to lung cancer
  • predisposition gene for pancreatic ductal adenocarcinoma
  • Variant & Polymorphism SNP , other
  • missense mutations were significantly elevated in breast cancer
  • at single nucleotide polymorphism sites (-4518A>G, IVS21-77C>T, IVS61-55T>C and IVS62+60G>A) the ATTA haplotype showed significantly increased risk of lung cancer compared with the GCCA haplotype
  • missense substitutions in ATM confer increased risk of breast cancer
  • Candidate gene should be further evaluated as a biomarker for the early detection of esophageal cancer and tobacco use in patients
    Marker
    Therapy target
    SystemTypeDisorderPubmed
    cancer  
    modulation of ATM kinase activity can be beneficial for increasing radiosensitivity of cells, and therefore may be beneficial in increasing the efficacy of currently available cancer therapeutics
    cardiovascularaquired 
    may be a new therapeutic target for cardiovascular pathologies
    ANIMAL & CELL MODELS
    Atm-/-mice