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ATM (ataxia telangiectasia mutated)

Identity

HGNC (Hugo) ATM
LocusID (NCBI) 472
Location 11q22.3
Location_base_pair Starts at 108093559 and ends at 108239826 bp from pter ( according to hg19-Feb_2009)  [Mapping]
Note see also, in Deep Insight section: Ataxia-Telangiectasia and variants

DNA/RNA

 
  ATM (11q22.3) in normal cells: PAC 1053F10 - Courtesy Mariano Rocchi, Resources for Molecular Cytogenetics.
Description 66 exons spanning 184 kb of genomic DNA; numerous Alu and Lime sequences
Transcription
  • alternative exons 1a and 1b; initiation codon lies within exon 4; 12 kb transcript with a 9.2 kb of coding sequence
  • The ATM promotor is bi-directional and also directs the transcription of the E14/NPAT/CAND3 gene
  • Protein

    Description 3056 amino acids; 350 kDa; contains a Pl 3-kinase-like domain (phosphatidylinositol 3-prime kinase)
    Expression found in all tissues
    Localisation mostly in the nucleus throughout all stages of the cell cycle
    Function initiates cell cycle checkpoints in response to double-strand DNA breaks by phosphorylating p53, BRCA1, H2AX,cAbl,IkB-alpha and chk1, as well as other targets; in certain types of tissues ATM inhibits radiation-induced, p53-dependent apoptosis.
    Homology phosphatidylinositol 3-kinase (PI3K)-like proteins, most closely related to ATR and the DNA-PK catalytic subunit

    Mutations

    Germinal various types of mutations have been described, dispersed throughout the gene, and therefore most patients are compound heterozygotes; most mutations appear to inactivate the ATM protein by truncation, large deletions, or annulation of initiation or termination, although missense mutations have been described in the PI3 kinase domain and the leucine zipper motif. Missense mutations outside of the PI3 kinase and leucine zipper domains have been described among breast cancer patients, although these mutations have not been found in A-T patients. Whether these mutations contribute to breast cancer though not to ataxia-telangiectasia remains controversial.
    Somatic biallelic mutation can occur in T-prolymphocytic leukaemia

    Implicated in

    Entity ataxia telangiectasia
    Disease ataxia telangiectasia is a progressive cerebellar degenerative disease with telangiectasia, immunodeficiency, cancer risk, radiosensitivity, and chromosomal instability
    Prognosis poor: median age at death:17 yrs; survival rarely exceeds 30 yrs, though survival is imcreasing with improved medical care
    Cytogenetics spontaneous chromatid/chromosome breaks; non clonal stable chromosome rearrangements involving immunoglobulin superfamilly genes e.g. inv(7)(p14q35); clonal rearrangements.
      

    Other Leukemias implicated (Data extracted from papers in the Atlas)

    Leukemias 11q23ChildAMLID1615 11q23ID1030 11q23secondLeukID1131 t1119ELLID1029 t0812q24q22ID2057
    t0814ID1050 8p11inMPDID1091 inv8p11q13ID1189

    External links

    Nomenclature
    HGNC (Hugo)ATM   795
    Cards
    AtlasATMID123
    Entrez_Gene (NCBI)ATM  472  ATM serine/threonine kinase
    GeneCards (Weizmann)ATM
    Ensembl hg19 (Hinxton)ENSG00000149311 [Gene_View]  chr11:108093559-108239826 [Contig_View]  ATM [Vega]
    Ensembl hg38 (Hinxton)ENSG00000149311 [Gene_View]  chr11:108093559-108239826 [Contig_View]  ATM [Vega]
    ICGC DataPortalENSG00000149311
    cBioPortalATM
    AceView (NCBI)ATM
    Genatlas (Paris)ATM
    WikiGenes472
    SOURCE (Princeton)ATM
    Genomic and cartography
    GoldenPath hg19 (UCSC)ATM  -     chr11:108093559-108239826 +  11q22-q23   [Description]    (hg19-Feb_2009)
    GoldenPath hg38 (UCSC)ATM  -     11q22-q23   [Description]    (hg38-Dec_2013)
    EnsemblATM - 11q22-q23 [CytoView hg19]  ATM - 11q22-q23 [CytoView hg38]
    Mapping of homologs : NCBIATM [Mapview hg19]  ATM [Mapview hg38]
    OMIM114480   208900   607585   
    Gene and transcription
    Genbank (Entrez)AB209133 AF035328 AK299843 BC007023 BC022307
    RefSeq transcript (Entrez)NM_000051 NM_138292 NM_138293
    RefSeq genomic (Entrez)AC_000143 NC_000011 NC_018922 NG_009830 NT_033899 NW_001838042 NW_004929381
    Consensus coding sequences : CCDS (NCBI)ATM
    Cluster EST : UnigeneHs.367437 [ NCBI ]
    CGAP (NCI)Hs.367437
    Alternative Splicing : Fast-db (Paris)GSHG0005224
    Alternative Splicing GalleryENSG00000149311
    Gene ExpressionATM [ NCBI-GEO ]     ATM [ SEEK ]   ATM [ MEM ]
    SOURCE (Princeton)Expression in : [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
    Protein : pattern, domain, 3D structure
    UniProt/SwissProtQ13315 (Uniprot)
    NextProtQ13315  [Medical]
    With graphics : InterProQ13315
    Splice isoforms : SwissVarQ13315 (Swissvar)
    Catalytic activity : Enzyme2.7.11.1 [ Enzyme-Expasy ]   2.7.11.12.7.11.1 [ IntEnz-EBI ]   2.7.11.1 [ BRENDA ]   2.7.11.1 [ KEGG ]   
    Domaine pattern : Prosite (Expaxy)FAT (PS51189)    FATC (PS51190)    PI3_4_KINASE_1 (PS00915)    PI3_4_KINASE_2 (PS00916)    PI3_4_KINASE_3 (PS50290)   
    Domains : Interpro (EBI)ARM-type_fold    ATM    FATC    Kinase-like_dom    PI3/4_kinase_cat_dom    PI3/4_kinase_CS    PIK-rel_kinase_FAT    PIK_FAT    TAN   
    Related proteins : CluSTrQ13315
    Domain families : Pfam (Sanger)FAT (PF02259)    FATC (PF02260)    PI3_PI4_kinase (PF00454)    TAN (PF11640)   
    Domain families : Pfam (NCBI)pfam02259    pfam02260    pfam00454    pfam11640   
    Domain families : Smart (EMBL)PI3Kc (SM00146)  
    DMDM Disease mutations472
    Blocks (Seattle)Q13315
    Human Protein AtlasENSG00000149311
    Peptide AtlasQ13315
    HPRD06347
    IPIIPI00298306   IPI00783886   IPI00816070   IPI00930438   IPI00977827   IPI00976048   IPI00977195   IPI00976623   IPI00977797   IPI00979647   
    Protein Interaction databases
    DIP (DOE-UCLA)Q13315
    IntAct (EBI)Q13315
    FunCoupENSG00000149311
    BioGRIDATM
    IntegromeDBATM
    STRING (EMBL)ATM
    Ontologies - Pathways
    QuickGOQ13315
    Ontology : AmiGOtelomere maintenance  double-strand break repair via homologous recombination  chromosome, telomeric region  response to hypoxia  somitogenesis  pre-B cell allelic exclusion  DNA binding  protein serine/threonine kinase activity  DNA-dependent protein kinase activity  protein binding  ATP binding  nucleoplasm  spindle  DNA repair  double-strand break repair  protein phosphorylation  cellular response to DNA damage stimulus  DNA damage induced protein phosphorylation  DNA damage response, signal transduction by p53 class mediator resulting in cell cycle arrest  cell cycle arrest  mitotic spindle assembly checkpoint  reciprocal meiotic recombination  signal transduction  brain development  heart development  intrinsic apoptotic signaling pathway in response to DNA damage  response to ionizing radiation  cytoplasmic membrane-bounded vesicle  1-phosphatidylinositol-3-kinase activity  peptidyl-serine phosphorylation  negative regulation of B cell proliferation  protein complex binding  histone serine kinase activity  histone-serine phosphorylation  phosphatidylinositol-3-phosphate biosynthetic process  lipoprotein catabolic process  positive regulation of apoptotic process  positive regulation of DNA damage response, signal transduction by p53 class mediator  positive regulation of neuron apoptotic process  protein autophosphorylation  protein dimerization activity  protein N-terminus binding  oocyte development  neuron apoptotic process  histone mRNA catabolic process  cellular response to gamma radiation  signal transduction involved in mitotic G2 DNA damage checkpoint  replicative senescence  
    Ontology : EGO-EBItelomere maintenance  double-strand break repair via homologous recombination  chromosome, telomeric region  response to hypoxia  somitogenesis  pre-B cell allelic exclusion  DNA binding  protein serine/threonine kinase activity  DNA-dependent protein kinase activity  protein binding  ATP binding  nucleoplasm  spindle  DNA repair  double-strand break repair  protein phosphorylation  cellular response to DNA damage stimulus  DNA damage induced protein phosphorylation  DNA damage response, signal transduction by p53 class mediator resulting in cell cycle arrest  cell cycle arrest  mitotic spindle assembly checkpoint  reciprocal meiotic recombination  signal transduction  brain development  heart development  intrinsic apoptotic signaling pathway in response to DNA damage  response to ionizing radiation  cytoplasmic membrane-bounded vesicle  1-phosphatidylinositol-3-kinase activity  peptidyl-serine phosphorylation  negative regulation of B cell proliferation  protein complex binding  histone serine kinase activity  histone-serine phosphorylation  phosphatidylinositol-3-phosphate biosynthetic process  lipoprotein catabolic process  positive regulation of apoptotic process  positive regulation of DNA damage response, signal transduction by p53 class mediator  positive regulation of neuron apoptotic process  protein autophosphorylation  protein dimerization activity  protein N-terminus binding  oocyte development  neuron apoptotic process  histone mRNA catabolic process  cellular response to gamma radiation  signal transduction involved in mitotic G2 DNA damage checkpoint  replicative senescence  
    Pathways : BIOCARTAcdc25 and chk1 Regulatory Pathway in response to DNA damage [Genes]    RB Tumor Suppressor/Checkpoint Signaling in response to DNA damage [Genes]    Role of BRCA1, BRCA2 and ATR in Cancer Susceptibility [Genes]    p53 Signaling Pathway [Genes]    ATM Signaling Pathway [Genes]    Apoptotic Signaling in Response to DNA Damage [Genes]    Cell Cycle: G1/S Check Point [Genes]    Hypoxia and p53 in the Cardiovascular system [Genes]    Cell Cycle: G2/M Checkpoint [Genes]    Regulation of cell cycle progression by Plk3 [Genes]   
    Pathways : KEGGNF-kappa B signaling pathway    FoxO signaling pathway    Cell cycle    p53 signaling pathway    Apoptosis    HTLV-I infection    Transcriptional misregulation in cancer    MicroRNAs in cancer   
    REACTOMEQ13315 [protein]
    REACTOME PathwaysREACT_115566 Cell Cycle [pathway]
    REACTOME PathwaysREACT_120956 Cellular responses to stress [pathway]
    REACTOME PathwaysREACT_216 DNA Repair [pathway]
    REACTOME PathwaysREACT_111183 Meiosis [pathway]
    Protein Interaction DatabaseATM
    DoCM (Curated mutations)ATM
    Wikipedia pathwaysATM
    Gene fusion - rearrangements
    Polymorphisms : SNP, variants
    NCBI Variation ViewerATM [hg38]
    dbSNP Single Nucleotide Polymorphism (NCBI)ATM
    dbVarATM
    ClinVarATM
    1000_GenomesATM 
    Exome Variant ServerATM
    SNP (GeneSNP Utah)ATM
    SNP : HGBaseATM
    Genetic variants : HAPMAPATM
    Genomic VariantsATM  ATM [DGVbeta]
    Mutations
    ICGC Data PortalENSG00000149311 
    Cancer Gene: CensusATM 
    Somatic Mutations in Cancer : COSMICATM 
    CONAN: Copy Number AnalysisATM 
    LOVD (Leiden Open Variation Database)Whole genome datasets
    LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
    LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
    LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
    LOVD (Leiden Open Variation Database)**PUBLIC** CCHMC Molecular Genetics Laboratory Mutation Database
    LOVD (Leiden Open Variation Database)MSeqDR-LSDB Mitochondrial Disease Locus Specific Database
    Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] 
    Diseases
    DECIPHER (Syndromes)11:108093559-108239826
    Mutations and Diseases : HGMDATM
    OMIM114480    208900    607585   
    MedgenATM
    NextProtQ13315 [Medical]
    GENETestsATM
    Disease Genetic AssociationATM
    Huge Navigator ATM [HugePedia]  ATM [HugeCancerGEM]
    snp3D : Map Gene to Disease472
    DGIdb (Drug Gene Interaction db)ATM
    General knowledge
    Homologs : HomoloGeneATM
    Homology/Alignments : Family Browser (UCSC)ATM
    Phylogenetic Trees/Animal Genes : TreeFamATM
    Chemical/Protein Interactions : CTD472
    Chemical/Pharm GKB GenePA61
    Clinical trialATM
    Cancer Resource (Charite)ENSG00000149311
    Other databases
    Other databasehttp://cancergenome.broadinstitute.org/index.php?tgene=ATM
    Probes
    ProbeATM (11q22.3)  in normal cells (Bari)
    Litterature
    PubMed499 Pubmed reference(s) in Entrez
    CoreMineATM
    GoPubMedATM
    iHOPATM

    Bibliography

    -
    Gorlin RJ et al
    Oxford Monogr Med Genet ..
     
    Cancer risks in A-T heterozygotes.
    Easton DF
    International journal of radiation biology. 1994 ; 66 (6 Suppl) : S177-S182.
    PMID 7836845
     
    TEL1, a gene involved in controlling telomere length in S. cerevisiae, is homologous to the human ataxia telangiectasia gene.
    Greenwell PW, Kronmal SL, Porter SE, Gassenhuber J, Obermaier B, Petes TD
    Cell. 1995 ; 82 (5) : 823-829.
    PMID 7671310
     
    The mei-41 gene of D. melanogaster is a structural and functional homolog of the human ataxia telangiectasia gene.
    Hari KL, Santerre A, Sekelsky JJ, McKim KS, Boyd JB, Hawley RS
    Cell. 1995 ; 82 (5) : 815-821.
    PMID 7671309
     
    A single ataxia telangiectasia gene with a product similar to PI-3 kinase.
    Savitsky K, Bar-Shira A, Gilad S, Rotman G, Ziv Y, Vanagaite L, Tagle DA, Smith S, Uziel T, Sfez S, Ashkenazi M, Pecker I, Frydman M, Harnik R, Patanjali SR, Simmons A, Clines GA, Sartiel A, Gatti RA, Chessa L, Sanal O, Lavin MF, Jaspers NG, Taylor AM, Arlett CF, Miki T, Weissman SM, Lovett M, Collins FS, Shiloh Y
    Science (New York, N.Y.). 1995 ; 268 (5218) : 1749-1753.
    PMID 7792600
     
    The complete sequence of the coding region of the ATM gene reveals similarity to cell cycle regulators in different species.
    Savitsky K, Sfez S, Tagle DA, Ziv Y, Sartiel A, Collins FS, Shiloh Y, Rotman G
    Human molecular genetics. 1995 ; 4 (11) : 2025-2032.
    PMID 8589678
     
    ATM-related genes: what do they tell us about functions of the human gene?
    Zakian VA
    Cell. 1995 ; 82 (5) : 685-687.
    PMID 7671296
     
    Atm-deficient mice: a paradigm of ataxia telangiectasia.
    Barlow C, Hirotsune S, Paylor R, Liyanage M, Eckhaus M, Collins F, Shiloh Y, Crawley JN, Ried T, Tagle D, Wynshaw-Boris A
    Cell. 1996 ; 86 (1) : 159-171.
    PMID 8689683
     
    The ataxia-telangiectasia gene product, a constitutively expressed nuclear protein that is not up-regulated following genome damage.
    Brown KD, Ziv Y, Sadanandan SN, Chessa L, Collins FS, Shiloh Y, Tagle DA
    Proceedings of the National Academy of Sciences of the United States of America. 1997 ; 94 (5) : 1840-1845.
    PMID 9050866
     
    Ataxia-telangiectasia locus: sequence analysis of 184 kb of human genomic DNA containing the entire ATM gene.
    Platzer M, Rotman G, Bauer D, Uziel T, Savitsky K, Bar-Shira A, Gilad S, Shiloh Y, Rosenthal A
    Genome research. 1997 ; 7 (6) : 592-605.
    PMID 9199932
     
    Ataxia-telangiectasia and the Nijmegen breakage syndrome: related disorders but genes apart.
    Shiloh Y
    Annual review of genetics. 1997 ; 31 : 635-662.
    PMID 9442910
     
    Biallelic mutations in the ATM gene in T-prolymphocytic leukemia.
    Stilgenbauer S, Schaffner C, Litterst A, Liebisch P, Gilad S, Bar-Shira A, James MR, Lichter P, Dˆhner H
    Nature medicine. 1997 ; 3 (10) : 1155-1159.
    PMID 9334731
     
    CAND3: a ubiquitously expressed gene immediately adjacent and in opposite transcriptional orientation to the ATM gene at 11q23.1.
    Chen X, Yang L, Udar N, Liang T, Uhrhammer N, Xu S, Bay JO, Wang Z, Dandakar S, Chiplunkar S, Klisak I, Telatar M, Yang H, Concannon P, Gatti RA
    Mammalian genome : official journal of the International Mammalian Genome Society. 1997 ; 8 (2) : 129-133.
    PMID 9060412
     
    Clustering of missense mutations in the ataxia-telangiectasia gene in a sporadic T-cell leukaemia.
    Vorechovskˆ‡ I, Luo L, Dyer MJ, Catovsky D, Amlot PL, Yaxley JC, Foroni L, Hammarstrˆm L, Webster AD, Yuille MA
    Nature genetics. 1997 ; 17 (1) : 96-99.
    PMID 9288106
     
    Cell-cycle signaling: Atm displays its many talents.
    Westphal CH
    Current biology : CB. 1997 ; 7 (12) : R789-R792.
    PMID 9382823
     
    Recombinant ATM protein complements the cellular A-T phenotype.
    Ziv Y, Bar-Shira A, Pecker I, Russell P, Jorgensen TJ, Tsarfati I, Shiloh Y
    Oncogene. 1997 ; 15 (2) : 159-167.
    PMID 9244351
     
    Ataxia-telangiectasia: identification and detection of founder-effect mutations in the ATM gene in ethnic populations.
    Telatar M, Teraoka S, Wang Z, Chun HH, Liang T, Castellvi-Bel S, Udar N, Borresen-Dale AL, Chessa L, Bernatowska-Matuszkiewicz E, Porras O, Watanabe M, Junker A, Concannon P, Gatti RA
    American journal of human genetics. 1998 ; 62 (1) : 86-97.
    PMID 9443866
     
    Requirements for p53 and the ATM gene product in the regulation of G1/S and S phase checkpoints.
    Xie G, Habbersett RC, Jia Y, Peterson SR, Lehnert BE, Bradbury EM, D'Anna JA
    Oncogene. 1998 ; 16 (6) : 721-736.
    PMID 9488036
     
    Breast cancer risk in ataxia telangiectasia (AT) heterozygotes: haplotype study in French AT families.
    Janin N, Andrieu N, Ossian K, Laugˆ© A, Croquette MF, Griscelli C, Debrˆ© M, Bressac-de-Paillerets B, Aurias A, Stoppa-Lyonnet D
    British journal of cancer. 1999 ; 80 (7) : 1042-1045.
    PMID 10362113
     
    ATM-heterozygous germline mutations contribute to breast cancer-susceptibility.
    Broeks A, Urbanus JH, Floore AN, Dahler EC, Klijn JG, Rutgers EJ, Devilee P, Russell NS, van Leeuwen FE, van 't Veer LJ
    American journal of human genetics. 2000 ; 66 (2) : 494-500.
    PMID 10677309
     
    ATM phosphorylates histone H2AX in response to DNA double-strand breaks.
    Burma S, Chen BP, Murphy M, Kurimasa A, Chen DJ
    The Journal of biological chemistry. 2001 ; 276 (45) : 42462-42467.
    PMID 11571274
     
    REVIEW articlesautomatic search in PubMed
    Last year publicationsautomatic search in PubMed

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    Contributor(s)

    Written04-1998Jean Loup Huret
    Updated10-1999Nancy Uhrhammer, Jacques-Olivier Bay and Richard A Gatti
    Updated11-2002Nancy Uhrhammer, Jacques-Olivier Bay and Richard A Gatti

    Citation

    This paper should be referenced as such :
    Uhrhammer, N ; Bay, JO ; Gatti, RA
    ATM (ataxia telangiectasia mutated)
    Atlas Genet Cytogenet Oncol Haematol. 2003;7(1):12-13.
    Free online version   Free pdf version   [Bibliographic record ]
    History of this paper:
    Uhrhammer, N ; Bay, JO ; Gatti, RA. ATM (ataxia telangiectasia mutated). Atlas Genet Cytogenet Oncol Haematol. 1999;3(4):173-174.
    http://documents.irevues.inist.fr/bitstream/2042/37550/1/10-1999-ATM123.pdf
    Uhrhammer, N ; Bay, JO ; Gatti, RA. ATM (ataxia telangiectasia mutated). Atlas Genet Cytogenet Oncol Haematol. 2003;7(1):12-13.
    http://documents.irevues.inist.fr/bitstream/2042/37923/1/11-2002-ATM123.pdf
    URL : http://AtlasGeneticsOncology.org/Genes/ATMID123.html

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