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ATM (ataxia telangiectasia mutated)

Written1998-04Jean-Loup Huret
Genetics, Dept Medical Information, University of Poitiers; CHU Poitiers Hospital, F-86021 Poitiers, France
Updated1999-10Nancy Uhrhammer, Jacques-Olivier Bay, Richard A Gatti
Centre Jean-Perrin, BP 392, 63000 Clermont-Ferrand, France
Updated2002-11Nancy Uhrhammer, Jacques-Olivier Bay, Richard A Gatti
Centre Jean-Perrin, BP 392, 63000 Clermont-Ferrand, France
Updated2016-10Yossi Shiloh
The David and Inez Myers Chair in Cancer Research, Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel; yossih@post.tau.ac.il

Abstract Review on ATM, with data on DNA, on the protein encoded, and where the gene is implicated.

(Note : for Links provided by Atlas : click)

Identity

Alias_namestelomere maintenance 1
homolog (S. cerevisiae)
Alias_symbol (synonym)TEL1
TELO1
HGNC (Hugo) ATM
LocusID (NCBI) 472
Atlas_Id 123
Location 11q22.3  [Link to chromosome band 11q22]
Location_base_pair Starts at 108093559 and ends at 108239826 bp from pter ( according to hg19-Feb_2009)  [Mapping ATM.png]
Fusion genes
(updated 2016)
ATM (11q22.3) / ASPH (8q12.3)ATM (11q22.3) / ATM (11q22.3)ATP6V1C2 (2p25.1) / ATM (11q22.3)
CUX1 (7q22.1) / ATM (11q22.3)JARID2 (6p22.3) / ATM (11q22.3)
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 The ATM gene extends over 184 kb and contains 66 exons producing a 13 kb mRNA (Uziel T et al., 1996; Platzer M et al., 1997); 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 NPAT gene.

Protein

Description ATM is a homeostatic protein kinase with an extremely broad range of roles in various cellular circuits (Shiloh Y et al., 2013; Guleria A et al., 2016; Shiloh Y, 2014; Cremona CA et al., 2014; Ambrose M et al., 2013; Espach Y et al., 2015; Awasthi P et al., 2016). This large polypeptide of 350 kDa and 3,056 residues bears a PI3 kinase signature within its carboxy-terminal catalytic site, but has the catalytic activity of a serine-threonine protein kinase. This motif is characteristic of a protein family of which ATM is a member - the PI-3 kinase-like protein kinases (PIKKs; Lovejoy CA et al., 2009; Baretić D et al., 2014).
This family also contains the MTOR protein, which regulates many signaling pathways in response to nutrient levels, growth factors and energy balance (Alayev A et al., 2013; Cornu M et al., 2013); the catalytic subunit of the DNA-dependent protein kinase (DNA-PKcs), which is involved in the NHEJ pathway of double strand breaks (DSB) repair and other genotoxic stress responses (Davis AJ et al., 2014; Jette N et al., 2015), SMG1, which plays a key role in nonsense-mediated mRNA decay (Yamashita A, 2013); and ATR, which responds to stalled replication forks and a variety of DNA lesions that lead to the formation of single-stranded DNA, including deeply resected DSBs (Errico A et al., 2012; Maréchal A et al., 2013; Awasthi P et al., 2016). The redundancy, crosstalk and collaboration between the latter three PIKKs, which collectively respond to a broad spectrum of genotoxic stresses, are being extensively investigated (Lovejoy CA et al., 2009; Maréchal A et al., 2013; Sirbu BM et al., 2013; Thompson LH, 2012; Gobbini E et al., 2013; Chen BP et al., 2012).
It should be noted that in A-T patients, the two PIKKs that converse and cooperate with ATM in the response to genotoxic stress, ATR and DNA-PK, remain active. In view of the functional relationships between the three protein kinases, some of ATM's duties are probably carried out to a certain extent by ATR and/or DNA-PK, in A-T cells. On the other hand, the lack of a very versatile member of this trio may lead to some suboptimal responses of the other two, if they depend on the crosstalk with ATM. This interesting question is a subject of intensive research.
Expression ATM is expressed in all tissues.
Localisation Mostly in the nucleus throughout all stages of the cell cycle.
Function Homeostatic protein kinase involved in many cellular circuits. A primary role in the DNA damage response. Activated vigorously by DNA double-strand breaks and activates a broad network of responses. ATM initiates cell cycle checkpoints in response to double-strand DNA breaks by phosphorylating TP53, BRCA1, H2AFX ID: 40783, ABL1,NFKBIA and , as well as other targets; in certain types of tissues ATM inhibits radiation-induced, TP53-dependent apoptosis.
  • Double strand breaks. The most widely documented function of ATM, and the one associated with its most vigorous activation, is the mobilization of the complex signaling network that responds to DSBs in the DNA (Shiloh Y et al., 2013; Cremona CA et al., 2014; Awasthi P et al., 2016; Thompson LH, 2012; McKinnon PJ, 2012). DSBs are induced by exogenous DNA breaking agents or endogenous reactive oxygen species (Schieber M et al., 2014), and are an integral part of physiological processes including meiotic recombination (Borde V et al., 2013; Lange J et al., 2011) and the rearrangement of antigen receptor genes in the adaptive immune system (Alt FW et al., 2013). DSBs are repaired via nonhomologous end-joining (NHEJ), or homologous recombination repair (HRR; Shibata A et al., 2014; Chapman JR et al., 2012; Jasin M et al., 2013; Radhakrishnan SK et al., 2014). DSBs also activates the DDR, a vast signaling network that mobilizes special cell cycle checkpoints, extensively alters the cellular transcriptome, and changes the turnover, activity and function of numerous proteins that ultimately leads to modulation of numerous cellular circuits. This network is based on a core of dedicated DDR players and the ad-hoc recruitment of proteins from many other arenas of cellular metabolism, which typically undergo special, damage-induced post-translational modifications (PTMs; Shiloh Y et al., 2013; Sirbu BM et al., 2013; Thompson LH, 2012) (Goodarzi AA et al., 2013; Panier S et al., 2013; Polo SE et al., 2011).
    Once ATM mobilizes the vast DDR network in response to a DSB (McKinnon PJ, 2012; Shiloh Y et al., 2013; Bhatti S et al., 2011), its protein kinase activity is rapidly enhanced, and PTMs on the ATM molecule are induced, including several autophosphorylations and an acetylation (Shiloh Y et al., 2013; Bhatti S et al., 2011; Bakkenist CJ et al., 2003; Kozlov SV et al., 2006; Bensimon A et al., 2010; Sun Y et al., 2007; Kaidi A et al., 2013; Paull TT, 2015).
    ATM subsequently phosphorylates key players in various arms of the DSB response network (Shiloh Y et al., 2013; Bensimon A et al., 2010; Matsuoka S et al., 2007; Mu JJ et al., 2007; Bensimon A et al., 2011), including other protein kinases that in turn phosphorylate still other targets (Bensimon A et al., 2011).
  • Single-strand break repair and base excision repair. A broader, overarching role for ATM in maintaining genome stability was recently suggested in addition to mobilizing the DSB response (Shiloh Y, 2014). According to this conjecture, ATM supports other DNA repair pathways that respond to various genotoxic stresses, among them single-strand break repair (SSBR; Khoronenkova SV et al., 2015) and base excision repair (BER) - a cardinal pathway in dealing with the daily nuclear and mitochondrial DNA damage caused by endogenous agents (Wallace SS, 2014; Bauer NC et al., 2015).
    ATM's involvement in these processes is based on its ability to phosphorylate proteins that function in these pathways. In this way ATM also takes part also in resolving non-canonical DNA structures that arise in DNA metabolism, and in regulating other aspects of genome integrity such as nucleotide metabolism, the response to replication stress, and resolution of the occasional conflicts that arise between DNA damage and the transcription machinery. ATM is not critical for any of these processes in the same way it is for the DSB response, but rather contributes to their regulation (in most cases, their enhancement) when the need arises (Shiloh Y, 2014; Segal-Raz H et al., 2011; Zolner AE et al., 2011).
    This function of ATM may explain the moderate, variable sensitivity of ATM-deficient cells to a broad range of DNA damaging agents. Among them are UV radiation, alkylating agents, crosslinking agents, hydrogen peroxide, 4-Nitroquinoline 1-oxide, phorbol-12-myristate-13-acetate and topoisomerase 1 poisons (Yi M et al., 1990; Ward AJ et al., 1994; Hoar DI et al., 1976; Paterson MC et al., 1976; Smith PJ et al., 1980; Mirzayans R et al., 1989; Henderson EE et al., 1980; Scudiero DA, 1980; Jaspers NG et al., 1982; Teo IA et al., 1982; Barfknecht TR et al., 1982; Fedier A et al., 2003; Leonard JC et al., 2004; Lee JH et al., 2006; Zhang N et al., 1996; Smith PJ et al., 1989; Alagoz M et al., 2013; Katyal S et al., 2014; Speit G et al., 2000; Shiloh Y et al., 1985; Hannan MA et al., 2002).
    ATM-deficient cells also exhibit reduced efficiency in resolving TOP1 (Topoisomerase I) -DNA covalent intermediates (Alagoz M et al., 2013; Katyal S et al., 2014).
    This ongoing role of ATM is its routine function in the daily maintenance of genome stability, while its powerful role in the DSB response is reserved for when this harmful lesion interferes with the daily life of a cell. Thus, when ATM is missing, not only is there markedly reduced response to DSBs, the ongoing modulation of numerous pathways in response to occasional stresses becomes suboptimal. All of these lesions are part of the daily wear and tear on the genome that contributes to ageing.
    An additional role for ATM in genome dynamics was proposed following evidence that ATM is involved in shaping the epigenome in neurons by regulating the localization of the histone deacetylase 4 (HDAC4; Li J et al., 2012; Herrup K et al., 2013; Herrup K, 2013), targeting the EZH2 component of the polycomb repressive complex 2 (Li J et al., 2013), and regulating the levels of 5-hydroxymethylcytosine in Purkinje cells (Jiang D et al., 2015).
  • Oxidative stress/Cellular homeostasis.
    Cytoplasmic fraction of ATM. ATM's role in cellular homeostasis is further expanded by its cytoplasmic fraction. Specifically, cytoplasmic ATM was found to be associated with peroxisomes (Watters D et al., 1999; Tripathi DN et al., 2016; Zhang J et al., 2015) and mitochondria (Valentin-Vega YA et al., 2012). In view of the evidence of increased oxidative stress in ATM-deficient cells, it has long been suspected that ATM senses and responds to oxidative stress (Gatei M et al., 2001; Rotman G et al., 1997; Rotman G et al., 1997; Barzilai A et al., 2002; Watters DJ, 2003; Takao N et al., 2000; Alexander A et al., 2010). This conjecture was validated by work from the Paull lab (Guo Z et al., 2010a), which identified an MRN-independent mode of ATM activation, differentiating it from DSB-induced activation, stimulated by reactive oxygen species (ROS) and leading to ATM oxidation (Paull TT, 2015; Guo Z et al., 2010a; Guo Z et al., 2010b; Lee JH et al., 2014). ATM was also found to be involved specifically in the protection against oxidative stress induced by oxidized low-density lipoprotein (Semlitsch M et al., 2011). It has thus assumed the role of a redox sensor (Ditch S et al., 2012; Tripathi DN et al., 2016; Krüger A et al., 2011). Recently, the first phospho-proteomic screen was carried out to identify substrates of ROS-activated ATM (Kozlov SV et al., 2016). An important arm of the ATM-mediated response to ROS extends to peroxisomes (Tripathi DN et al., 2016). Work from the Walker lab showed that ROS-mediated activation of peroxisomal ATM leads to ATM-mediated phosphorylation of LKB and subsequent activation of AMPK and TSC2, which dampens mTORC1-mediated signaling, eventually decreasing protein synthesis and enhancing autophagy (Alexander A et al., 2010; Tripathi DN et al., 2013; Zhang J et al., 2013; Alexander A et al., 2010; Alexander A et al., 2010). Further work from this lab (Zhang J et al., 2015) showed that ATM also phosphorylates the peroxisomal protein PEX5, flagging it for ubiquitylation and subsequent binding to the autophagy adapter, SQSTM1 (p62), in the process of autophagy-associated peroxisome degradation (pexophagy) - a critical process in peroxisome homeostasis (Till A et al., 2012).
    Mitochondrial fraction of ATM. Still another arm of the ATM-mediated response to oxidative stress operates in the mitochondrial fraction of ATM. ATM is thus emerging also as a regulator of mitochondrial homeostasis. Evidence is accumulating of its involvement in mitochondrial function, mitophagy, and the integrity of mitochondrial DNA (Valentin-Vega YA et al., 2012; Ambrose M et al., 2007; Eaton JS et al., 2007; Fu X et al., 2008; Valentin-Vega YA et al., 2012; D'Souza AD et al., 2013; Sharma NK et al., 2014) and further work is needed to identify its substrates in mitochondria and the mechanistic aspects of its action in this arena.
  • Links between ATM and the SASP (senescence-associated secretory phenotype). Several laboratories recently described direct links between ATM and the SASP - a cardinal feature of cell senescence. Work from the Gamble lab (Chen H et al., 2015) showed that the histone variant macroH2A.1 is required for full transcriptional activation of SASP-promoting genes, driving a positive feedback loop that enhances cell senescence. This response is countered by a negative feedback loop that involves ATM activation by endoplasmic reticulum stress, elevated ROS levels or DNA damage. ATM's activity is required for the removal of macroH2A.1 from sites of SASP genes, thus leading to SASP gene repression. The Elledge lab identified a major SASP activator - the transcription factor GATA4, whose stabilization drives this process (Kang C et al., 2015). Importantly, the activation of this pathway was dependent on both ATM and ATR, as was senescence-associated activation of TP53 and CDKN2A (p16INK4a). On the other hand, the Zhang lab (Aird KM et al., 2015) recently showed that when cell senescence is induced by replication stress (e.g., following nucleotide deficiency), ATM inactivation allows the cell to bypass senescence by shifting cellular metabolism: upon ATM loss, dNTP levels rise due to up-regulation of the pentose phosphate pathway, whose key regulator, glucose-6-phosphate dehydrogenase (G6PD) is under functional regulation by ATM (Aird KM et al., 2015; Cosentino C et al., 2011).
  • Insulin response and lipoprotein metabolism. Other metabolic arenas in which ATM involvement is gaining attention are insulin response and lipoprotein metabolism, clinically represented by the metabolic syndrome. This role of ATM in cellular physiology was recently thoroughly and convincingly reviewed (Espach Y et al., 2015). Briefly, ATM was found to participate in several signaling pathways mediated by insulin (Yang DQ et al., 2000; Miles PD et al., 2007; Viniegra JG et al., 2005; Halaby MJ et al., 2008; Jeong I et al., 2010); and heterozygosity for Atm null allele in ApoE-deficient mice was found to aggravate their metabolic syndrome (Wu D et al., 2005; Schneider JG et al., 2006; Mercer JR et al., 2010), an effect that was partly relieved by the mitochondria-targeted antioxidant MitQ (Mercer JR et al., 2012.
  • IGF-1 receptor. Another pathway by which ATM may impact on cellular senescence is the dependence of IGF1R (IGF-1 receptor) expression on ATM (Peretz S et al., 2001; Goetz EM et al., 2011; Ching JK et al., 2013); the mechanism remains to be elucidated, but ATM impacts on IGF-1-mediated pathways, including those that affect cellular senescence (Luo X et al., 2014).
  • Beta-adrenergic receptor. Another series of observations assigned ATM a protective role in cardiac myocyte apoptosis stimulated by β-adrenergic receptor and myocardial remodeling. Loss of Atm in mice induced myocardial fibrosis and myocyte hypertrophy and interfered with cardiac remodeling following myocardial infarction (Foster CR et al., 2011; Foster CR et al., 2012; Foster CR et al., 2013; Daniel LL et al., 2014). The mechanistic aspects of these effects are still unclear, but ATM's apparent involvement in myocardial homeostasis might be relevant to the observation of elevated arteriosclerosis in A-T carriers (Swift M et al., 1983; Su Y et al., 2000).
  • Homology Phosphatidylinositol 3-kinase (PI3K)-like proteins, most closely related to ATR and the DNA-PK catalytic subunit.

    Mutations

    Note The cellular phenotype of A-T represents genome instability, deficient DNA damage response (DDR), and elevated oxidative stress, in addition to a premature senescence component (Shiloh Y et al., 1982).
    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.
    Patients with the severe form of A-T are homozygous or compound heterozygous for null ATM alleles. The corresponding mutations usually lead to truncation of the ATM protein and subsequently to its loss due to instability of the truncated derivatives; a smaller portion of the mutations create amino acid substitutions that abolish ATM's catalytic activity (Taylor AM et al., 2015; Gilad S et al., 1996; Sandoval N et al., 1999; Barone G et al., 2009) (see also http://chromium.liacs.nl/LOVD2/home.php?select_db=ATM).
    Careful inspection of the neurological symptoms of A-T patients reveals variability in their age of onset and rate of progression among patients with different combinations of null ATM alleles (Taylor AM et al., 2015; Crawford TO et al., 2000; Alterman N et al., 2007). Thus, despite the identical outcome in terms of ATM function, additional genes may affect the most cardinal symptom of A-T. Other, milder types of ATM mutations further extend this variability, and account for forms of the disease with extremely variable severity and age of onset of symptoms. The corresponding ATM genotypes are combinations of hypomorphic alleles or combinations of null and hypomorphic ones. Many of the latter are leaky splicing mutations and others are missense mutations, eventually yielding low amounts of active ATM (Taylor AM et al., 2015; Alterman N et al., 2007; Soresina A et al., 2008; Verhagen MM et al., 2009; Silvestri G et al., 2010; Saunders-Pullman R et al., 2012; Verhagen MM et al., 2012; Worth PF et al., 2013; Claes K et al., 2013; Méneret A et al., 2014; Nakamura K et al., 2014; Gilad S et al., 1998).
    Somatic B A variety of missense somatic, biallelic mutations were identified in hematologic malignancies, most notably mantle cell lymphoma and T-prolymphocytic leukaemia.
    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.

    Implicated in

    Note
    Entity Ataxia telangiectasia
    Note Ataxia telangiectasia is a prototype genome instability syndrome (Perlman SL et al., 2012; Lavin MF, 2008; Crawford TO, 1998; Chun HH et al., 2004; Taylor AM et al., 1982; Taylor AM et al., 2015; Taylor AM, 1978; Butterworth SV et al., 1986; Kennaugh AA et al., 1986).
    Disease Ataxia telangiectasia is a progressive cerebellar degenerative disease with telangiectasia, immunodeficiency, premature aging , cancer risk, radiosensitivity, and chromosomal instability.
    Prognosis Prognosis is poor: median age at death: 17 years; survival rarely exceeds 30 years, though survival is increasing 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.
      

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    Citation

    This paper should be referenced as such :
    Shiloh Y
    ATM (ataxia telangiectasia mutated);
    Atlas Genet Cytogenet Oncol Haematol. in press
    On line version : http://AtlasGeneticsOncology.org/Genes/ATMID123.html
    History of this paper:
    Huret, JL. ATM (ataxia telangiectasia mutated). Atlas Genet Cytogenet Oncol Haematol. 1998;2(3):77-78.
    http://documents.irevues.inist.fr/bitstream/handle/2042/37430/04-1998-ATM123.pdf
    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/handle/2042/37550/10-1999-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/handle/2042/37923/11-2002-ATM123.pdf


    Other Leukemias implicated (Data extracted from papers in the Atlas) [ 23 ]
      Classification of B-cell chronic lymphoproliferative disorders (CLD)
    Chronic lymphocytic leukaemia (CLL)
    Chronic myelogenous leukaemia (CML)
    del(11q) in non-Hodgkin's lymphoma (NHL)
    dic(9;17)(p13;q11) PAX5/TAOK1
    Small lymphocytic lymphoma
    t(1;3)(q25;q27) GAS5/BCL6
    t(3;3)(q27;q27) ST6GAL1/BCL6::del(3)(q27q27) ST6GAL1/BCL6
    t(3;6)(q27;p22) HIST1H4I/BCL6
    t(3;6)(q27;q14) SNHG5/BCL6
    t(3;6)(q27;q15) ?/BCL6
    t(3;7)(q27;q32) FRA7H/BCL6
    t(3;9)(q27;p13) GRHPR/BCL6
    t(3;9)(q27;p24) DMRT1/BCL6
    t(3;11)(q27;q23) POU2AF1/BCL6
    t(3;12)(q27;p12) LRMP/BCL6
    t(3;14)(q27;q32) HSP90AA1/BCL6
    t(3;19)(q27;q13) NAPA/BCL6
    t(6;9)(p22;q34) DEK/NUP214
    Classification of T-Cell disorders
    T-cell/histiocyte rich large B-cell lymphoma
    T-cell prolymphocytic leukemia (T-PLL)
    t(X;14)(q28;q11.2) TRA-TRD/MTCP1::t(X;7)(q28;q34) TRB/MTCP1


    Other Solid tumors implicated (Data extracted from papers in the Atlas) [ 3 ]
      Breast tumors : an overview
    Breast: Ductal carcinoma
    Pancreatic tumors: an overview


    Other Cancer prone implicated (Data extracted from papers in the Atlas) [ 2 ]
      Ataxia telangiectasia Hereditary breast cancer


    External links

    Nomenclature
    HGNC (Hugo)ATM   795
    LRG (Locus Reference Genomic)LRG_135
    Cards
    AtlasATMID123
    Entrez_Gene (NCBI)ATM  472  ATM serine/threonine kinase
    AliasesAT1; ATA; ATC; ATD; 
    ATDC; ATE; TEL1; TELO1
    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
    TCGA cBioPortalATM
    AceView (NCBI)ATM
    Genatlas (Paris)ATM
    WikiGenes472
    SOURCE (Princeton)ATM
    Genetics Home Reference (NIH)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 AF035326 AF035327 AF035328 AK299843
    RefSeq transcript (Entrez)NM_000051 NM_138292 NM_138293
    RefSeq genomic (Entrez)NC_000011 NC_018922 NG_009830 NT_033899 NW_004929381
    Consensus coding sequences : CCDS (NCBI)ATM
    Cluster EST : UnigeneHs.367437 [ NCBI ]
    CGAP (NCI)Hs.367437
    Alternative Splicing GalleryENSG00000149311
    Gene ExpressionATM [ NCBI-GEO ]   ATM [ EBI - ARRAY_EXPRESS ]   ATM [ SEEK ]   ATM [ MEM ]
    Gene Expression Viewer (FireBrowse)ATM [ Firebrowse - Broad ]
    SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
    GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
    BioGPS (Tissue expression)472
    GTEX Portal (Tissue expression)ATM
    Protein : pattern, domain, 3D structure
    UniProt/SwissProtQ13315   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
    NextProtQ13315  [Sequence]  [Exons]  [Medical]  [Publications]
    With graphics : InterProQ13315
    Splice isoforms : SwissVarQ13315
    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 ]   
    PhosPhoSitePlusQ13315
    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/Tel1    FATC_dom    Kinase-like_dom    PI3/4_kinase_cat_dom    PI3/4_kinase_CS    PIK-rel_kinase_FAT    PIK_FAT    TAN   
    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)  
    Conserved Domain (NCBI)ATM
    DMDM Disease mutations472
    Blocks (Seattle)ATM
    SuperfamilyQ13315
    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
    STRING (EMBL)ATM
    ZODIACATM
    Ontologies - Pathways
    QuickGOQ13315
    Ontology : AmiGOdouble-strand break repair via homologous recombination  DNA double-strand break processing  DNA synthesis involved in DNA repair  strand displacement  chromosome, telomeric region  nuclear chromosome, telomeric region  response to hypoxia  somitogenesis  pre-B cell allelic exclusion  DNA binding  protein serine/threonine kinase activity  protein serine/threonine kinase activity  DNA-dependent protein kinase activity  protein binding  ATP binding  nucleus  nucleoplasm  spindle  DNA replication  DNA repair  double-strand break repair via nonhomologous end joining  protein phosphorylation  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  telomere maintenance via telomerase  cell cycle arrest  mitotic spindle assembly checkpoint  reciprocal meiotic recombination  signal transduction  brain development  heart development  determination of adult lifespan  intrinsic apoptotic signaling pathway in response to DNA damage  response to ionizing radiation  regulation of autophagy  cytoplasmic, membrane-bounded vesicle  1-phosphatidylinositol-3-kinase activity  histone phosphorylation  peptidyl-serine phosphorylation  negative regulation of B cell proliferation  positive regulation of telomere maintenance via telomerase  protein complex binding  positive regulation of histone phosphorylation  V(D)J recombination  phosphatidylinositol-3-phosphate biosynthetic process  peptidyl-serine autophosphorylation  lipoprotein catabolic process  regulation of apoptotic process  positive regulation of apoptotic process  positive regulation of DNA damage response, signal transduction by p53 class mediator  positive regulation of neuron apoptotic process  meiotic telomere clustering  protein autophosphorylation  protein dimerization activity  protein N-terminus binding  oocyte development  neuron apoptotic process  regulation of telomerase activity  histone mRNA catabolic process  cellular response to gamma radiation  cellular response to nitrosative stress  signal transduction involved in mitotic G2 DNA damage checkpoint  replicative senescence  establishment of RNA localization to telomere  establishment of macromolecular complex localization to telomere  regulation of cellular response to heat  regulation of signal transduction by p53 class mediator  negative regulation of TORC1 signaling  negative regulation of telomere capping  positive regulation of telomere maintenance via telomere lengthening  positive regulation of telomerase catalytic core complex assembly  DNA repair complex  
    Ontology : EGO-EBIdouble-strand break repair via homologous recombination  DNA double-strand break processing  DNA synthesis involved in DNA repair  strand displacement  chromosome, telomeric region  nuclear chromosome, telomeric region  response to hypoxia  somitogenesis  pre-B cell allelic exclusion  DNA binding  protein serine/threonine kinase activity  protein serine/threonine kinase activity  DNA-dependent protein kinase activity  protein binding  ATP binding  nucleus  nucleoplasm  spindle  DNA replication  DNA repair  double-strand break repair via nonhomologous end joining  protein phosphorylation  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  telomere maintenance via telomerase  cell cycle arrest  mitotic spindle assembly checkpoint  reciprocal meiotic recombination  signal transduction  brain development  heart development  determination of adult lifespan  intrinsic apoptotic signaling pathway in response to DNA damage  response to ionizing radiation  regulation of autophagy  cytoplasmic, membrane-bounded vesicle  1-phosphatidylinositol-3-kinase activity  histone phosphorylation  peptidyl-serine phosphorylation  negative regulation of B cell proliferation  positive regulation of telomere maintenance via telomerase  protein complex binding  positive regulation of histone phosphorylation  V(D)J recombination  phosphatidylinositol-3-phosphate biosynthetic process  peptidyl-serine autophosphorylation  lipoprotein catabolic process  regulation of apoptotic process  positive regulation of apoptotic process  positive regulation of DNA damage response, signal transduction by p53 class mediator  positive regulation of neuron apoptotic process  meiotic telomere clustering  protein autophosphorylation  protein dimerization activity  protein N-terminus binding  oocyte development  neuron apoptotic process  regulation of telomerase activity  histone mRNA catabolic process  cellular response to gamma radiation  cellular response to nitrosative stress  signal transduction involved in mitotic G2 DNA damage checkpoint  replicative senescence  establishment of RNA localization to telomere  establishment of macromolecular complex localization to telomere  regulation of cellular response to heat  regulation of signal transduction by p53 class mediator  negative regulation of TORC1 signaling  negative regulation of telomere capping  positive regulation of telomere maintenance via telomere lengthening  positive regulation of telomerase catalytic core complex assembly  DNA repair complex  
    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 PathwaysR-HSA-75148 ATM mediated phosphorylation of repair proteins [pathway]
    REACTOME PathwaysR-HSA-69601 Ubiquitin Mediated Degradation of Phosphorylated Cdc25A [pathway]
    REACTOME PathwaysR-HSA-2559586 DNA Damage/Telomere Stress Induced Senescence [pathway]
    REACTOME PathwaysR-HSA-912446 Meiotic recombination [pathway]
    REACTOME PathwaysR-HSA-419552 Regulation of the Fanconi anemia pathway [pathway]
    REACTOME PathwaysR-HSA-83542 ATM mediated response to DNA double-strand break [pathway]
    REACTOME PathwaysR-HSA-69473 G2/M DNA damage checkpoint [pathway]
    REACTOME PathwaysR-HSA-349425 Autodegradation of the E3 ubiquitin ligase COP1 [pathway]
    REACTOME PathwaysR-HSA-69541 Stabilization of p53 [pathway]
    REACTOME PathwaysR-HSA-75154 Recruitment of repair and signaling proteins to double-strand breaks [pathway]
    REACTOME PathwaysR-HSA-3371453 Regulation of HSF1-mediated heat shock response [pathway]
    NDEx NetworkATM
    Atlas of Cancer Signalling NetworkATM
    Wikipedia pathwaysATM
    Orthology - Evolution
    OrthoDB472
    GeneTree (enSembl)ENSG00000149311
    Phylogenetic Trees/Animal Genes : TreeFamATM
    HOVERGENQ13315
    HOGENOMQ13315
    Homologs : HomoloGeneATM
    Homology/Alignments : Family Browser (UCSC)ATM
    Gene fusions - Rearrangements
    Fusion : MitelmanJARID2/ATM [6p22.3/11q22.3]  [t(6;11)(p22;q22)]  
    Fusion: TCGAJARID2 6p22.3 ATM 11q22.3 LUAD
    Polymorphisms : SNP and Copy number variants
    NCBI Variation ViewerATM [hg38]
    dbSNP Single Nucleotide Polymorphism (NCBI)ATM
    dbVarATM
    ClinVarATM
    1000_GenomesATM 
    Exome Variant ServerATM
    ExAC (Exome Aggregation Consortium)ATM (select the gene name)
    Genetic variants : HAPMAP472
    Genomic Variants (DGV)ATM [DGVbeta]
    DECIPHER (Syndromes)11:108093559-108239826  ENSG00000149311
    CONAN: Copy Number AnalysisATM 
    Mutations
    ICGC Data PortalATM 
    TCGA Data PortalATM 
    Broad Tumor PortalATM
    OASIS PortalATM [ Somatic mutations - Copy number]
    Cancer Gene: CensusATM 
    Somatic Mutations in Cancer : COSMICATM  [overview]  [genome browser]  [tissue]  [distribution]  
    Mutations and Diseases : HGMDATM
    intOGen PortalATM
    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
    BioMutasearch ATM
    DgiDB (Drug Gene Interaction Database)ATM
    DoCM (Curated mutations)ATM (select the gene name)
    CIViC (Clinical Interpretations of Variants in Cancer)ATM (select a term)
    intoGenATM
    NCG5 (London)ATM
    Cancer3DATM(select the gene name)
    Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
    Diseases
    OMIM114480    208900    607585   
    Orphanet104    22485    22484    10899    10693   
    MedgenATM
    Genetic Testing Registry ATM
    NextProtQ13315 [Medical]
    TSGene472
    GENETestsATM
    Huge Navigator ATM [HugePedia]
    snp3D : Map Gene to Disease472
    BioCentury BCIQATM
    ClinGenATM
    Clinical trials, drugs, therapy
    Chemical/Protein Interactions : CTD472
    Chemical/Pharm GKB GenePA61
    Clinical trialATM
    Miscellaneous
    canSAR (ICR)ATM (select the gene name)
    Probes
    Litterature
    PubMed499 Pubmed reference(s) in Entrez
    GeneRIFsGene References Into Functions (Entrez)
    CoreMineATM
    EVEXATM
    GoPubMedATM
    iHOPATM
    REVIEW articlesautomatic search in PubMed
    Last year publicationsautomatic search in PubMed

    Search in all EBI   NCBI

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    indexed on : Thu Nov 24 09:28:12 CET 2016

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