ID:ATM_HUMAN DESCRIPTION: RecName: Full=Serine-protein kinase ATM; EC=2.7.11.1; AltName: Full=Ataxia telangiectasia mutated; Short=A-T mutated; FUNCTION: Serine/threonine protein kinase which activates checkpoint signaling upon double strand breaks (DSBs), apoptosis and genotoxic stresses such as ionizing ultraviolet A light (UVA), thereby acting as a DNA damage sensor. Recognizes the substrate consensus sequence [ST]-Q. Phosphorylates 'Ser-139' of histone variant H2AX/H2AFX at double strand breaks (DSBs), thereby regulating DNA damage response mechanism. Also plays a role in pre-B cell allelic exclusion, a process leading to expression of a single immunoglobulin heavy chain allele to enforce clonality and monospecific recognition by the B-cell antigen receptor (BCR) expressed on individual B-lymphocytes. After the introduction of DNA breaks by the RAG complex on one immunoglobulin allele, acts by mediating a repositioning of the second allele to pericentromeric heterochromatin, preventing accessibility to the RAG complex and recombination of the second allele. Also involved in signal transduction and cell cycle control. May function as a tumor suppressor. Necessary for activation of ABL1 and SAPK. Phosphorylates DYRK2, CHEK2, p53/TP53, FANCD2, NFKBIA, BRCA1, CTIP, nibrin (NBN), TERF1, RAD9 and DCLRE1C. May play a role in vesicle and/or protein transport. Could play a role in T-cell development, gonad and neurological function. Plays a role in replication-dependent histone mRNA degradation. Binds DNA ends. Phosphorylation of DYRK2 in nucleus in response to genotoxic stress prevents its MDM2-mediated ubiquitination and subsequent proteasome degradation. CATALYTIC ACTIVITY: ATP + a protein = ADP + a phosphoprotein. ENZYME REGULATION: Inhibited by wortmannin. SUBUNIT: Dimers or tetramers in inactive state. On DNA damage, autophosphorylation dissociates ATM into monomers rendering them catalytically active. Binds p53/TP53, ABL1, BRCA1, NBN/nibrin and TERF1. Part of the BRCA1-associated genome surveillance complex (BASC), which contains BRCA1, MSH2, MSH6, MLH1, ATM, BLM, PMS2 and the RAD50-MRE11-NBN protein complex. This association could be a dynamic process changing throughout the cell cycle and within subnuclear domains. Interacts with RAD17; DNA damage promotes the association. Interacts with EEF1E1; the interaction, induced on DNA damage, up-regulates TP53. Interacts with DCLRE1C, KAT8, KAT5, NABP2, ATMIN and CEP164. Interacts with AP2B1 and AP3B2; the interaction occurs in cytoplasmic vesicles (By similarity). Interacts with TELO2 and TTI1. Interacts with DDX1. INTERACTION: Q9NY61:AATF; NbExp=3; IntAct=EBI-495465, EBI-372428; Q14676:MDC1; NbExp=2; IntAct=EBI-495465, EBI-495644; Q9BQ15:NABP2; NbExp=4; IntAct=EBI-495465, EBI-2120336; Q9Y4R8:TELO2; NbExp=4; IntAct=EBI-495465, EBI-1043674; P54274:TERF1; NbExp=2; IntAct=EBI-495465, EBI-710997; P54274-2:TERF1; NbExp=5; IntAct=EBI-495465, EBI-711018; O43156:TTI1; NbExp=5; IntAct=EBI-495465, EBI-1055680; SUBCELLULAR LOCATION: Nucleus. Cytoplasmic vesicle. Note=Primarily nuclear. Found also in endocytic vesicles in association with beta-adaptin. TISSUE SPECIFICITY: Found in pancreas, kidney, skeletal muscle, liver, lung, placenta, brain, heart, spleen, thymus, testis, ovary, small intestine, colon and leukocytes. INDUCTION: By ionizing radiation. DOMAIN: The FATC domain is required for interaction with KAT5. PTM: Phosphorylated by NUAK1/ARK5. Autophosphorylation on Ser-367, Ser-1893, Ser-1981 correlates with DNA damage-mediated activation of the kinase. PTM: Acetylation, on DNA damage, is required for activation of the kinase activity, dimer-monomer transition, and subsequent autophosphorylation on Ser-1981. Acetylated in vitro by KAT5/TIP60. DISEASE: Defects in ATM are the cause of ataxia telangiectasia (AT) [MIM:208900]; also known as Louis-Bar syndrome, which includes four complementation groups: A, C, D and E. This rare recessive disorder is characterized by progressive cerebellar ataxia, dilation of the blood vessels in the conjunctiva and eyeballs, immunodeficiency, growth retardation and sexual immaturity. AT patients have a strong predisposition to cancer; about 30% of patients develop tumors, particularly lymphomas and leukemias. Cells from affected individuals are highly sensitive to damage by ionizing radiation and resistant to inhibition of DNA synthesis following irradiation. DISEASE: Note=Defects in ATM contribute to T-cell acute lymphoblastic leukemia (TALL) and T-prolymphocytic leukemia (TPLL). TPLL is characterized by a high white blood cell count, with a predominance of prolymphocytes, marked splenomegaly, lymphadenopathy, skin lesions and serous effusion. The clinical course is highly aggressive, with poor response to chemotherapy and short survival time. TPLL occurs both in adults as a sporadic disease and in younger AT patients. DISEASE: Note=Defects in ATM contribute to B-cell non-Hodgkin lymphomas (BNHL), including mantle cell lymphoma (MCL). DISEASE: Note=Defects in ATM contribute to B-cell chronic lymphocytic leukemia (BCLL). BCLL is the commonest form of leukemia in the elderly. It is characterized by the accumulation of mature CD5+ B-lymphocytes, lymphadenopathy, immunodeficiency and bone marrow failure. SIMILARITY: Belongs to the PI3/PI4-kinase family. ATM subfamily. SIMILARITY: Contains 1 FAT domain. SIMILARITY: Contains 1 FATC domain. SIMILARITY: Contains 1 PI3K/PI4K domain. SEQUENCE CAUTION: Sequence=AAA86520.1; Type=Erroneous initiation; Note=Translation N-terminally extended; Sequence=AAA86520.1; Type=Miscellaneous discrepancy; Note=Probable cloning artifact; Sequence=AAI37170.1; Type=Erroneous initiation; Note=Translation N-terminally extended; Sequence=AAI37170.1; Type=Miscellaneous discrepancy; Note=Probable cloning artifact; Sequence=EAW67111.1; Type=Erroneous gene model prediction; WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and Haematology; URL="http://atlasgeneticsoncology.org/Genes/ATM123.html"; WEB RESOURCE: Name=GeneReviews; URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/ATM"; WEB RESOURCE: Name=NIEHS-SNPs; URL="http://egp.gs.washington.edu/data/atm/"; WEB RESOURCE: Name=Wikipedia; Note=Ataxia telangiectasia mutated entry; URL="http://en.wikipedia.org/wiki/Ataxia_telangiectasia_mutated";
The RNAfold program from the Vienna RNA Package is used to perform the secondary structure predictions and folding calculations. The estimated folding energy is in kcal/mol. The more negative the energy, the more secondary structure the RNA is likely to have.
Pfam Domains: PF00454 - Phosphatidylinositol 3- and 4-kinase PF02259 - FAT domain PF02260 - FATC domain PF11640 - Telomere-length maintenance and DNA damage repair
SCOP Domains: 48371 - ARM repeat 56112 - Protein kinase-like (PK-like)
ModBase Predicted Comparative 3D Structure on Q13315
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Orthologous Genes in Other Species
Orthologies between human, mouse, and rat are computed by taking the best BLASTP hit, and filtering out non-syntenic hits. For more distant species reciprocal-best BLASTP hits are used. Note that the absence of an ortholog in the table below may reflect incomplete annotations in the other species rather than a true absence of the orthologous gene.
Biological Process: GO:0000077 DNA damage checkpoint GO:0000723 telomere maintenance GO:0000724 double-strand break repair via homologous recombination GO:0000729 DNA double-strand break processing GO:0001541 ovarian follicle development GO:0001666 response to hypoxia GO:0001756 somitogenesis GO:0002331 pre-B cell allelic exclusion GO:0002376 immune system process GO:0002377 immunoglobulin production GO:0006260 DNA replication GO:0006281 DNA repair GO:0006303 double-strand break repair via nonhomologous end joining GO:0006468 protein phosphorylation GO:0006915 apoptotic process GO:0006974 cellular response to DNA damage stimulus GO:0006975 DNA damage induced protein phosphorylation GO:0006977 DNA damage response, signal transduction by p53 class mediator resulting in cell cycle arrest GO:0007049 cell cycle GO:0007050 cell cycle arrest GO:0007094 mitotic spindle assembly checkpoint GO:0007131 reciprocal meiotic recombination GO:0007140 male meiosis GO:0007143 female meiotic division GO:0007165 signal transduction GO:0007292 female gamete generation GO:0007420 brain development GO:0007507 heart development GO:0008340 determination of adult lifespan GO:0008585 female gonad development GO:0008630 intrinsic apoptotic signaling pathway in response to DNA damage GO:0009791 post-embryonic development GO:0010212 response to ionizing radiation GO:0010506 regulation of autophagy GO:0016310 phosphorylation GO:0016572 histone phosphorylation GO:0018105 peptidyl-serine phosphorylation GO:0030889 negative regulation of B cell proliferation GO:0032210 regulation of telomere maintenance via telomerase GO:0032212 positive regulation of telomere maintenance via telomerase GO:0033129 positive regulation of histone phosphorylation GO:0033151 V(D)J recombination GO:0035264 multicellular organism growth GO:0036092 phosphatidylinositol-3-phosphate biosynthetic process GO:0036289 peptidyl-serine autophosphorylation GO:0042159 lipoprotein catabolic process GO:0042981 regulation of apoptotic process GO:0043065 positive regulation of apoptotic process GO:0043517 positive regulation of DNA damage response, signal transduction by p53 class mediator GO:0043525 positive regulation of neuron apoptotic process GO:0045141 meiotic telomere clustering GO:0046777 protein autophosphorylation GO:0048538 thymus development GO:0048599 oocyte development GO:0051402 neuron apoptotic process GO:0051726 regulation of cell cycle GO:0070192 chromosome organization involved in meiotic cell cycle GO:0071044 histone mRNA catabolic process GO:0071480 cellular response to gamma radiation GO:0071481 cellular response to X-ray GO:0071500 cellular response to nitrosative stress GO:0072434 signal transduction involved in mitotic G2 DNA damage checkpoint GO:0090399 replicative senescence GO:0097694 establishment of RNA localization to telomere GO:0097695 establishment of macromolecular complex localization to telomere GO:1900034 regulation of cellular response to heat GO:1901216 positive regulation of neuron death GO:1901796 regulation of signal transduction by p53 class mediator GO:1903626 positive regulation of DNA catabolic process GO:1903978 regulation of microglial cell activation GO:1904262 negative regulation of TORC1 signaling GO:1904354 negative regulation of telomere capping GO:1904358 positive regulation of telomere maintenance via telomere lengthening GO:1904884 positive regulation of telomerase catalytic core complex assembly GO:2001022 positive regulation of response to DNA damage stimulus GO:0051972 regulation of telomerase activity
BioCarta from NCI Cancer Genome Anatomy Project h_cdc25Pathway - cdc25 and chk1 Regulatory Pathway in response to DNA damage h_rbPathway - RB Tumor Suppressor/Checkpoint Signaling in response to DNA damage h_atrbrcaPathway - Role of BRCA1, BRCA2 and ATR in Cancer Susceptibility h_p53Pathway - p53 Signaling Pathway h_atmPathway - ATM Signaling Pathway h_chemicalPathway - Apoptotic Signaling in Response to DNA Damage h_g1Pathway - Cell Cycle: G1/S Check Point h_p53hypoxiaPathway - Hypoxia and p53 in the Cardiovascular system h_g2Pathway - Cell Cycle: G2/M Checkpoint h_plk3Pathway - Regulation of cell cycle progression by Plk3
Reactome (by CSHL, EBI, and GO)
Protein Q13315 (Reactome details) participates in the following event(s):
R-HSA-5682026 MRN bound to shortened telomeres activates ATM R-HSA-5686410 BLM mediates dissolution of double Holliday junction R-HSA-5686657 ERCC1:XPF cleaves flaps generated by SSA R-HSA-5693540 MRN activates ATM R-HSA-5693589 D-loop dissociation and strand annealing R-HSA-5693599 Association of Ku heterodimer with ends of DNA double-strand break R-HSA-5693598 ATM phosphorylates NBN R-HSA-5684081 MRN complex binds CDK2 and RBBP8 R-HSA-5693602 ATM recognizes H2AFX-Nucleosomes R-HSA-5684071 RNF4 ubiquitinates MDC1 R-HSA-5685838 CX3 complex binds D-loop structures R-HSA-5693620 D-loop formation mediated by PALB2, BRCA2 and RAD51 R-HSA-69889 Phosphorylation and activation of Chk1 by ATM R-HSA-349444 Phosphorylation of COP1 at Ser-387 by ATM R-HSA-349455 Phosphorylation of MDM4 by ATM R-HSA-5686578 Activated ATM phosphorylates ABL1 R-HSA-5693609 ATM phosphorylates TP53 at S15 R-HSA-6798372 ATM phosphorylates DYRK2 R-HSA-6799097 ATM phosphorylates ZNF420 R-HSA-6800490 ATM phosphorylates PIDD1 R-HSA-6804276 ATM phosphorylates TTC5 R-HSA-6804955 ATM phosphorylates MDM2 R-HSA-5682044 KAT5 acetylates ATM at DNA DSBs R-HSA-5693612 MRN complex bound to DNA ends recruits ATM R-HSA-5682018 MRN complex bound to shortened telomeres recruits ATM R-HSA-3371567 DBC1 is phosphorylated by ATM/ART R-HSA-6792712 KAT5 acetylates ATM at shortened telomeres R-HSA-5693583 MDC1 associates with gamma-H2AFX at nuclear foci R-HSA-5683967 EYA1-4 dephosphorylates tyrosine Y142 of H2AFX R-HSA-5683986 APBB1 and MAPK8 bind diphosphorylated H2AFX R-HSA-5693549 ATM phosphorylates histone H2AFX on S139 at DNA DSBs R-HSA-5684096 CDK2 phosphorylates RBBP8 R-HSA-5684140 ATM phosphorylates RBBP8 R-HSA-5693608 Initial resection of double-strand break ends R-HSA-5684108 BRCA1 binds phosphorylated RBBP8 R-HSA-5693542 Association of RPA complexes with ssDNA at resected DNA DSBs R-HSA-5685994 Long-range resection of DNA DSBs by EXO1 or DNA2 R-HSA-5685341 BCDX2 complex stabilizes RAD51 filament R-HSA-5693561 RAD51 binds BRCA2 at resected DNA DSBs R-HSA-5693593 D-loop extension by DNA polymerases R-HSA-5685985 EXO1 or DNA2 in complex with BLM or WRN binds initially resected DNA DSBs along with BRIP1 recruitment R-HSA-5693584 Cleavage of Holliday junctions by GEN1 or SLX1A:SLX4:MUS81:EME1,(MUS81:EME2) R-HSA-5686440 MUS81:EME1,EME2 cleaves D-loop R-HSA-5682967 WHSC1 binds DNA DSBs R-HSA-5693536 ATM phosphorylates MDC1 R-HSA-5683964 ATM phosphorylates EYA1-4 R-HSA-5684875 Binding of ATR:ATRIP to RPA at resected DNA DSBs R-HSA-5682983 ATM phosphorylates WHSC1 R-HSA-5682965 WHSC1 dimethylates histone H4 on lysine K21 at DSBs R-HSA-5682992 KDM4A,B bind H4K20Me2 R-HSA-5685011 ATR activation at DNA DSBs R-HSA-5684887 Activation of CHEK1 at resected DNA DSBs R-HSA-5684882 CHEK1 is recruited to resected DNA DSBs R-HSA-5693580 Association of RAD52 with the RPA complex at resected DNA DSBs R-HSA-5685156 ATR phosphorylates RPA2 R-HSA-5682588 RNF8 binds phosphorylated MDC1 at DNA DSBs R-HSA-5693566 TP53BP1 associates with H4K20Me2 at DNA DSBs R-HSA-5683077 RNF8 and RNF168 ubiquitinate KDM4A,B R-HSA-5693564 Association of RAD51 with RAD52:DNA double-strand break ends R-HSA-5682586 HERC2 and PIAS4 are recruited to DNA DSBs R-HSA-5682629 HERC2 facilitates UBE2N:UBE2V2 binding to RNF8 R-HSA-5682607 PIAS4 SUMOylates HERC2 with SUMO1 at DNA DSBs R-HSA-5682863 RNF168 binds DNA DSBs R-HSA-5682858 RNF8 and RNF168 ubiquitinate H2AFX R-HSA-5683384 UIMC1 and FAM175A bind DNA DSBs R-HSA-5683405 PPP5C dephosphorylates TP53BP1 R-HSA-5683425 ATM phosphorylates TP53BP1 at DNA DSBs R-HSA-6799332 ATR phosphorylates TP53 R-HSA-5686642 RAD52 promotes single strand annealing at resected DNA DSBs R-HSA-5682598 ATM phosphorylates HERC2 R-HSA-5693551 Phosphorylation of BRCA1-A complex at multiple sites by ATM R-HSA-5683385 Formation of BRCA1-A complex at DNA DSBs R-HSA-5683735 CHEK2 is recruited to DNA DSBs R-HSA-5683801 CHEK2 phosphorylates BRCA1 R-HSA-69891 Phosphorylation and activation of CHEK2 by ATM R-HSA-5684052 PIAS4 SUMOylates MDC1 R-HSA-5686685 RIF1 and PAX1IP bind TP53BP1 at DNA DSBs R-HSA-5686900 TP53BP1 recruits DCLRE1C to ATM R-HSA-5686704 Activated ATM phosphorylates DCLRE1C R-HSA-912446 Meiotic recombination R-HSA-2559586 DNA Damage/Telomere Stress Induced Senescence R-HSA-5693568 Resolution of D-loop Structures through Holliday Junction Intermediates R-HSA-5685938 HDR through Single Strand Annealing (SSA) R-HSA-5693548 Sensing of DNA Double Strand Breaks R-HSA-5693554 Resolution of D-loop Structures through Synthesis-Dependent Strand Annealing (SDSA) R-HSA-5693571 Nonhomologous End-Joining (NHEJ) R-HSA-6796648 TP53 Regulates Transcription of DNA Repair Genes R-HSA-1500620 Meiosis R-HSA-5693565 Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks R-HSA-5693607 Processing of DNA double-strand break ends R-HSA-5693579 Homologous DNA Pairing and Strand Exchange R-HSA-2559583 Cellular Senescence R-HSA-5693537 Resolution of D-Loop Structures R-HSA-5693567 HDR through Homologous Recombination (HR) or Single Strand Annealing (SSA) R-HSA-5693606 DNA Double Strand Break Response R-HSA-5693532 DNA Double-Strand Break Repair R-HSA-69601 Ubiquitin Mediated Degradation of Phosphorylated Cdc25A R-HSA-349425 Autodegradation of the E3 ubiquitin ligase COP1 R-HSA-69541 Stabilization of p53 R-HSA-6804757 Regulation of TP53 Degradation R-HSA-6804756 Regulation of TP53 Activity through Phosphorylation R-HSA-6803204 TP53 Regulates Transcription of Genes Involved in Cytochrome C Release R-HSA-6803207 TP53 Regulates Transcription of Caspase Activators and Caspases R-HSA-6804760 Regulation of TP53 Activity through Methylation R-HSA-3371453 Regulation of HSF1-mediated heat shock response R-HSA-3700989 Transcriptional Regulation by TP53 R-HSA-1474165 Reproduction R-HSA-1640170 Cell Cycle R-HSA-5693616 Presynaptic phase of homologous DNA pairing and strand exchange R-HSA-5685942 HDR through Homologous Recombination (HRR) R-HSA-2262752 Cellular responses to stress R-HSA-5693538 Homology Directed Repair R-HSA-73894 DNA Repair R-HSA-69610 p53-Independent DNA Damage Response R-HSA-69563 p53-Dependent G1 DNA Damage Response R-HSA-6806003 Regulation of TP53 Expression and Degradation R-HSA-5633007 Regulation of TP53 Activity R-HSA-5633008 TP53 Regulates Transcription of Cell Death Genes R-HSA-3371556 Cellular response to heat stress R-HSA-212436 Generic Transcription Pathway R-HSA-8953897 Cellular responses to external stimuli R-HSA-69613 p53-Independent G1/S DNA damage checkpoint R-HSA-69580 p53-Dependent G1/S DNA damage checkpoint R-HSA-73857 RNA Polymerase II Transcription R-HSA-69615 G1/S DNA Damage Checkpoints R-HSA-74160 Gene expression (Transcription) R-HSA-69620 Cell Cycle Checkpoints R-HSA-69473 G2/M DNA damage checkpoint R-HSA-69481 G2/M Checkpoints
US Server
Sequence and Links to Tools and Databases 
Common Gene Haplotype Alleles 
