ID ATR_HUMAN Reviewed; 2644 AA.
AC Q13535; Q59HB2; Q7KYL3; Q93051; Q9BXK4;
DT 29-MAR-2005, integrated into UniProtKB/Swiss-Prot.
DT 05-JUL-2004, sequence version 3.
DT 01-MAY-2013, entry version 122.
DE RecName: Full=Serine/threonine-protein kinase ATR;
DE EC=2.7.11.1;
DE AltName: Full=Ataxia telangiectasia and Rad3-related protein;
DE AltName: Full=FRAP-related protein 1;
GN Name=ATR; Synonyms=FRP1;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RX PubMed=8978690;
RA Bentley N.J., Holtzman D.A., Flaggs G., Keegan K.S., DeMaggio A.,
RA Ford J.C., Hoekstra M., Carr A.M.;
RT "The Schizosaccharomyces pombe rad3 checkpoint gene.";
RL EMBO J. 15:6641-6651(1996).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND TISSUE SPECIFICITY.
RC TISSUE=T-cell;
RX PubMed=8610130; DOI=10.1073/pnas.93.7.2850;
RA Cimprich K.A., Shin T.B., Keith C.T., Schreiber S.L.;
RT "cDNA cloning and gene mapping of a candidate human cell cycle
RT checkpoint protein.";
RL Proc. Natl. Acad. Sci. U.S.A. 93:2850-2855(1996).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA] OF 433-526 (ISOFORMS 1 AND
RP 2), AND TISSUE SPECIFICITY.
RX PubMed=11470508; DOI=10.1016/S0378-1119(01)00543-1;
RA Mannino J.L., Kim W.-J., Wernick M., Nguyen S.V., Braquet R.,
RA Adamson A.W., Den Z., Batzer M.A., Collins C.C., Brown K.D.;
RT "Evidence for alternate splicing within the mRNA transcript encoding
RT the DNA damage response kinase ATR.";
RL Gene 272:35-43(2001).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 2155-2644 (ISOFORM 3).
RC TISSUE=Brain;
RA Totoki Y., Toyoda A., Takeda T., Sakaki Y., Tanaka A., Yokoyama S.,
RA Ohara O., Nagase T., Kikuno R.F.;
RL Submitted (MAR-2005) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY.
RX PubMed=8843195;
RA Keegan K.S., Holtzman D.A., Plug A.W., Christenson E.R.,
RA Brainerd E.E., Flaggs G., Bentley N.J., Taylor E.M., Meyn M.S.,
RA Moss S.B., Carr A.M., Ashley T., Hoekstra M.F.;
RT "The Atr and Atm protein kinases associate with different sites along
RT meiotically pairing chromosomes.";
RL Genes Dev. 10:2423-2437(1996).
RN [6]
RP ENZYME REGULATION.
RX PubMed=9766667;
RA Sarkaria J.N., Tibbetts R.S., Busby E.C., Kennedy A.P., Hill D.E.,
RA Abraham R.T.;
RT "Inhibition of phosphoinositide 3-kinase related kinases by the
RT radiosensitizing agent wortmannin.";
RL Cancer Res. 58:4375-4382(1998).
RN [7]
RP FUNCTION, AUTOPHOSPHORYLATION, AND MUTAGENESIS OF ASP-2475.
RX PubMed=9427750; DOI=10.1093/emboj/17.1.159;
RA Cliby W.A., Roberts C.J., Cimprich K.A., Stringer C.M., Lamb J.R.,
RA Schreiber S.L., Friend S.H.;
RT "Overexpression of a kinase-inactive ATR protein causes sensitivity to
RT DNA-damaging agents and defects in cell cycle checkpoints.";
RL EMBO J. 17:159-169(1998).
RN [8]
RP FUNCTION, AND MUTAGENESIS OF ASP-2494.
RX PubMed=9636169; DOI=10.1073/pnas.95.13.7445;
RA Wright J.A., Keegan K.S., Herendeen D.R., Bentley N.J., Carr A.M.,
RA Hoekstra M.F., Concannon P.;
RT "Protein kinase mutants of human ATR increase sensitivity to UV and
RT ionizing radiation and abrogate cell cycle checkpoint control.";
RL Proc. Natl. Acad. Sci. U.S.A. 95:7445-7450(1998).
RN [9]
RP INTERACTION WITH HDAC2, AND IDENTIFICATION IN A COMPLEX CONTAINING
RP HDAC2 AND CHD4.
RX PubMed=10545197; DOI=10.1021/bi991614n;
RA Schmidt D.R., Schreiber S.L.;
RT "Molecular association between ATR and two components of the
RT nucleosome remodeling and deacetylating complex, HDAC2 and CHD4.";
RL Biochemistry 38:14711-14717(1999).
RN [10]
RP FUNCTION, AND MUTAGENESIS OF LYS-2327 AND ASP-2475.
RX PubMed=9925639;
RA Tibbetts R.S., Brumbaugh K.M., Williams J.M., Sarkaria J.N.,
RA Cliby W.A., Shieh S.-Y., Taya Y., Prives C., Abraham R.T.;
RT "A role for ATR in the DNA damage-induced phosphorylation of p53.";
RL Genes Dev. 13:152-157(1999).
RN [11]
RP COFACTOR, AND FUNCTION.
RX PubMed=10608806; DOI=10.1074/jbc.274.53.37538;
RA Kim S.-T., Lim D.-S., Canman C.E., Kastan M.B.;
RT "Substrate specificities and identification of putative substrates of
RT ATM kinase family members.";
RL J. Biol. Chem. 274:37538-37543(1999).
RN [12]
RP FUNCTION, AUTOPHOSPHORYLATION, MUTAGENESIS OF ASP-2494, AND ENZYME
RP REGULATION.
RX PubMed=10597277; DOI=10.1038/sj.onc.1203077;
RA Hall-Jackson C.A., Cross D.A.E., Morrice N., Smythe C.;
RT "ATR is a caffeine-sensitive, DNA-activated protein kinase with a
RT substrate specificity distinct from DNA-PK.";
RL Oncogene 18:6707-6713(1999).
RN [13]
RP FUNCTION.
RX PubMed=10859164;
RA Liu Q., Guntuku S., Cui X.-S., Matsuoka S., Cortez D., Tamai K.,
RA Luo G., Carattini-Rivera S., DeMayo F., Bradley A., Donehower L.A.,
RA Elledge S.J.;
RT "Chk1 is an essential kinase that is regulated by Atr and required for
RT the G(2)/M DNA damage checkpoint.";
RL Genes Dev. 14:1448-1459(2000).
RN [14]
RP FUNCTION, SUBCELLULAR LOCATION, AND MUTAGENESIS OF LYS-2327.
RX PubMed=11114888; DOI=10.1101/gad.851000;
RA Tibbetts R.S., Cortez D., Brumbaugh K.M., Scully R., Livingston D.,
RA Elledge S.J., Abraham R.T.;
RT "Functional interactions between BRCA1 and the checkpoint kinase ATR
RT during genotoxic stress.";
RL Genes Dev. 14:2989-3002(2000).
RN [15]
RP FUNCTION.
RX PubMed=11673449; DOI=10.1074/jbc.C100569200;
RA Ward I.M., Chen J.;
RT "Histone H2AX is phosphorylated in an ATR-dependent manner in response
RT to replicational stress.";
RL J. Biol. Chem. 276:47759-47762(2001).
RN [16]
RP FUNCTION, AND INTERACTION WITH RAD17.
RX PubMed=11418864; DOI=10.1038/35082110;
RA Bao S., Tibbetts R.S., Brumbaugh K.M., Fang Y., Richardson D.A.,
RA Ali A., Chen S.M., Abraham R.T., Wang X.-F.;
RT "ATR/ATM-mediated phosphorylation of human Rad17 is required for
RT genotoxic stress responses.";
RL Nature 411:969-974(2001).
RN [17]
RP FUNCTION, SUBCELLULAR LOCATION, AND INTERACTION WITH ATRIP.
RX PubMed=11721054; DOI=10.1126/science.1065521;
RA Cortez D., Guntuku S., Qin J., Elledge S.J.;
RT "ATR and ATRIP: partners in checkpoint signaling.";
RL Science 294:1713-1716(2001).
RN [18]
RP FUNCTION.
RX PubMed=12526805; DOI=10.1016/S0092-8674(02)01113-3;
RA Casper A.M., Nghiem P., Arlt M.F., Glover T.W.;
RT "ATR regulates fragile site stability.";
RL Cell 111:779-789(2002).
RN [19]
RP FUNCTION, AND SUBCELLULAR LOCATION.
RX PubMed=11865061; DOI=10.1128/MCB.22.6.1834-1843.2002;
RA Hammond E.M., Denko N.C., Dorie M.J., Abraham R.T., Giaccia A.J.;
RT "Hypoxia links ATR and p53 through replication arrest.";
RL Mol. Cell. Biol. 22:1834-1843(2002).
RN [20]
RP DNA-BINDING, AND MUTAGENESIS OF LYS-2327.
RX PubMed=12011431; DOI=10.1073/pnas.102167799;
RA Uensal-Kacmaz K., Makhov A.M., Griffith J.D., Sancar A.;
RT "Preferential binding of ATR protein to UV-damaged DNA.";
RL Proc. Natl. Acad. Sci. U.S.A. 99:6673-6678(2002).
RN [21]
RP FUNCTION, SUBCELLULAR LOCATION, AND MUTAGENESIS OF ASP-2475.
RX PubMed=12814551; DOI=10.1016/S0960-9822(03)00376-2;
RA Barr S.M., Leung C.G., Chang E.E., Cimprich K.A.;
RT "ATR kinase activity regulates the intranuclear translocation of ATR
RT and RPA following ionizing radiation.";
RL Curr. Biol. 13:1047-1051(2003).
RN [22]
RP INTERACTION WITH CLSPN.
RX PubMed=12766152; DOI=10.1074/jbc.M301136200;
RA Chini C.C.S., Chen J.;
RT "Human claspin is required for replication checkpoint control.";
RL J. Biol. Chem. 278:30057-30062(2003).
RN [23]
RP FUNCTION, INTERACTION WITH MSH2, AND MASS SPECTROMETRY.
RX PubMed=14657349; DOI=10.1073/pnas.2536810100;
RA Wang Y., Qin J.;
RT "MSH2 and ATR form a signaling module and regulate two branches of the
RT damage response to DNA methylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 100:15387-15392(2003).
RN [24]
RP FUNCTION, DNA-BINDING, AND IDENTIFICATION IN A COMPLEX WITH RPA AND
RP ATRIP.
RX PubMed=12791985; DOI=10.1126/science.1083430;
RA Zou L., Elledge S.J.;
RT "Sensing DNA damage through ATRIP recognition of RPA-ssDNA
RT complexes.";
RL Science 300:1542-1548(2003).
RN [25]
RP INTERACTION WITH BCR-ABL.
RX PubMed=15050919; DOI=10.1016/S1535-6108(04)00056-X;
RA Dierov J., Dierova R., Carroll M.;
RT "BCR/ABL translocates to the nucleus and disrupts an ATR-dependent
RT intra-S phase checkpoint.";
RL Cancer Cell 5:275-285(2004).
RN [26]
RP FUNCTION.
RX PubMed=14742437; DOI=10.1074/jbc.C300554200;
RA Ward I.M., Minn K., Chen J.;
RT "UV-induced ataxia-telangiectasia-mutated and Rad3-related (ATR)
RT activation requires replication stress.";
RL J. Biol. Chem. 279:9677-9680(2004).
RN [27]
RP DNA-BINDING, AND SUBCELLULAR LOCATION.
RX PubMed=14871897; DOI=10.1074/jbc.M314212200;
RA Dart D.A., Adams K.E., Akerman I., Lakin N.D.;
RT "Recruitment of the cell cycle checkpoint kinase ATR to chromatin
RT during S-phase.";
RL J. Biol. Chem. 279:16433-16440(2004).
RN [28]
RP FUNCTION.
RX PubMed=15314022; DOI=10.1101/gad.1196104;
RA Andreassen P.R., D'Andrea A.D., Taniguchi T.;
RT "ATR couples FANCD2 monoubiquitination to the DNA-damage response.";
RL Genes Dev. 18:1958-1963(2004).
RN [29]
RP FUNCTION.
RX PubMed=15496423; DOI=10.1093/hmg/ddh335;
RA Alderton G.K., Joenje H., Varon R., Borglum A.D., Jeggo P.A.,
RA O'Driscoll M.;
RT "Seckel syndrome exhibits cellular features demonstrating defects in
RT the ATR-signalling pathway.";
RL Hum. Mol. Genet. 13:3127-3138(2004).
RN [30]
RP FUNCTION, SUBUNIT, IDENTIFICATION IN A COMPLEX WITH ATRIP AND RPA1,
RP DNA-BINDING, AND ENZYME REGULATION.
RX PubMed=14729973; DOI=10.1128/MCB.24.3.1292-1300.2003;
RA Uensal-Kacmaz K., Sancar A.;
RT "Quaternary structure of ATR and effects of ATRIP and replication
RT protein A on its DNA binding and kinase activities.";
RL Mol. Cell. Biol. 24:1292-1300(2004).
RN [31]
RP FUNCTION.
RX PubMed=15210935; DOI=10.1073/pnas.0403410101;
RA Cortez D., Glick G., Elledge S.J.;
RT "Minichromosome maintenance proteins are direct targets of the ATM and
RT ATR checkpoint kinases.";
RL Proc. Natl. Acad. Sci. U.S.A. 101:10078-10083(2004).
RN [32]
RP INTERACTION WITH EEF1E1.
RX PubMed=15680327; DOI=10.1016/j.cell.2004.11.054;
RA Park B.-J., Kang J.W., Lee S.W., Choi S.-J., Shin Y.K., Ahn Y.H.,
RA Choi Y.H., Choi D., Lee K.S., Kim S.;
RT "The haploinsufficient tumor suppressor p18 upregulates p53 via
RT interactions with ATM/ATR.";
RL Cell 120:209-221(2005).
RN [33]
RP INTERACTION WITH ATRIP.
RX PubMed=15758953; DOI=10.1038/nature03442;
RA Falck J., Coates J., Jackson S.P.;
RT "Conserved modes of recruitment of ATM, ATR and DNA-PKcs to sites of
RT DNA damage.";
RL Nature 434:605-611(2005).
RN [34]
RP INTERACTION WITH CEP164, AND SUBCELLULAR LOCATION.
RX PubMed=18283122; DOI=10.1101/gad.1627708;
RA Sivasubramaniam S., Sun X., Pan Y.R., Wang S., Lee E.Y.;
RT "Cep164 is a mediator protein required for the maintenance of genomic
RT stability through modulation of MDC1, RPA, and CHK1.";
RL Genes Dev. 22:587-600(2008).
RN [35]
RP INVOLVEMENT IN SCKL1.
RX PubMed=12640452; DOI=10.1038/ng1129;
RA O'Driscoll M., Ruiz-Perez V.L., Woods C.G., Jeggo P.A., Goodship J.A.;
RT "A splicing mutation affecting expression of ataxia-telangiectasia and
RT Rad3-related protein (ATR) results in Seckel syndrome.";
RL Nat. Genet. 33:497-501(2003).
RN [36]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-428 AND THR-1989, AND
RP MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18691976; DOI=10.1016/j.molcel.2008.07.007;
RA Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R.,
RA Greff Z., Keri G., Stemmann O., Mann M.;
RT "Kinase-selective enrichment enables quantitative phosphoproteomics of
RT the kinome across the cell cycle.";
RL Mol. Cell 31:438-448(2008).
RN [37]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [38]
RP INTERACTION WITH TTI1.
RX PubMed=20810650; DOI=10.1101/gad.1934210;
RA Hurov K.E., Cotta-Ramusino C., Elledge S.J.;
RT "A genetic screen identifies the Triple T complex required for DNA
RT damage signaling and ATM and ATR stability.";
RL Genes Dev. 24:1939-1950(2010).
RN [39]
RP INTERACTION WITH TELO2.
RX PubMed=20801936; DOI=10.1101/gad.1956410;
RA Takai H., Xie Y., de Lange T., Pavletich N.P.;
RT "Tel2 structure and function in the Hsp90-dependent maturation of mTOR
RT and ATR complexes.";
RL Genes Dev. 24:2019-2030(2010).
RN [40]
RP INTERACTION WITH TELO2 AND TTI1.
RX PubMed=20427287; DOI=10.1074/jbc.M110.121699;
RA Kaizuka T., Hara T., Oshiro N., Kikkawa U., Yonezawa K., Takehana K.,
RA Iemura S., Natsume T., Mizushima N.;
RT "Tti1 and Tel2 are critical factors in mammalian target of rapamycin
RT complex assembly.";
RL J. Biol. Chem. 285:20109-20116(2010).
RN [41]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [42]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21406692; DOI=10.1126/scisignal.2001570;
RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J.,
RA Johansen P.T., Kratchmarova I., Kassem M., Mann M., Olsen J.V.,
RA Blagoev B.;
RT "System-wide temporal characterization of the proteome and
RT phosphoproteome of human embryonic stem cell differentiation.";
RL Sci. Signal. 4:RS3-RS3(2011).
RN [43]
RP VARIANTS [LARGE SCALE ANALYSIS] ALA-64; TYR-90; ASN-297; ILE-316;
RP MET-959; HIS-1087; GLY-1213; PRO-1488; ASN-1607; SER-1612; GLY-2002;
RP ALA-2120; ASP-2132; ILE-2233; GLN-2425; ALA-2434; LYS-2438 AND
RP GLN-2537.
RX PubMed=17344846; DOI=10.1038/nature05610;
RA Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C.,
RA Bignell G., Davies H., Teague J., Butler A., Stevens C., Edkins S.,
RA O'Meara S., Vastrik I., Schmidt E.E., Avis T., Barthorpe S.,
RA Bhamra G., Buck G., Choudhury B., Clements J., Cole J., Dicks E.,
RA Forbes S., Gray K., Halliday K., Harrison R., Hills K., Hinton J.,
RA Jenkinson A., Jones D., Menzies A., Mironenko T., Perry J., Raine K.,
RA Richardson D., Shepherd R., Small A., Tofts C., Varian J., Webb T.,
RA West S., Widaa S., Yates A., Cahill D.P., Louis D.N., Goldstraw P.,
RA Nicholson A.G., Brasseur F., Looijenga L., Weber B.L., Chiew Y.-E.,
RA DeFazio A., Greaves M.F., Green A.R., Campbell P., Birney E.,
RA Easton D.F., Chenevix-Trench G., Tan M.-H., Khoo S.K., Teh B.T.,
RA Yuen S.T., Leung S.Y., Wooster R., Futreal P.A., Stratton M.R.;
RT "Patterns of somatic mutation in human cancer genomes.";
RL Nature 446:153-158(2007).
RN [44]
RP VARIANT FCTCS ARG-2144.
RX PubMed=22341969; DOI=10.1016/j.ajhg.2012.01.007;
RA Tanaka A., Weinel S., Nagy N., O'Driscoll M., Lai-Cheong J.E.,
RA Kulp-Shorten C.L., Knable A., Carpenter G., Fisher S.A., Hiragun M.,
RA Yanase Y., Hide M., Callen J., McGrath J.A.;
RT "Germline mutation in ATR in autosomal- dominant oropharyngeal cancer
RT syndrome.";
RL Am. J. Hum. Genet. 90:511-517(2012).
CC -!- FUNCTION: Serine/threonine protein kinase which activates
CC checkpoint signaling upon genotoxic stresses such as ionizing
CC radiation (IR), ultraviolet light (UV), or DNA replication
CC stalling, thereby acting as a DNA damage sensor. Recognizes the
CC substrate consensus sequence [ST]-Q. Phosphorylates BRCA1, CHEK1,
CC MCM2, RAD17, RPA2, SMC1 and p53/TP53, which collectively inhibit
CC DNA replication and mitosis and promote DNA repair, recombination
CC and apoptosis. Phosphorylates 'Ser-139' of histone variant
CC H2AX/H2AFX at sites of DNA damage, thereby regulating DNA damage
CC response mechanism. Required for FANCD2 ubiquitination. Critical
CC for maintenance of fragile site stability and efficient regulation
CC of centrosome duplication.
CC -!- CATALYTIC ACTIVITY: ATP + a protein = ADP + a phosphoprotein.
CC -!- COFACTOR: Manganese.
CC -!- ENZYME REGULATION: Activated by DNA and inhibited by BCR-ABL
CC oncogene. Slightly activated by ATRIP. Inhibited by caffeine,
CC wortmannin and LY294002.
CC -!- SUBUNIT: Interacts with ATRIP (By similarity). Forms a heterodimer
CC with ATRIP. Binds to DNA, and to UV-damaged DNA with higher
CC affinity. Interacts with RAD17, MSH2 and HDAC2. Present in a
CC complex containing ATRIP and RPA-coated single-stranded DNA.
CC Present in a complex containing CHD4 and HDAC2. Interacts with
CC BCR-ABL after genotoxic stress. Interacts with EEF1E1. This
CC interaction is enhanced by UV irradiation. Interacts with CLSPN
CC and CEP164. Interacts with TELO2 and TTI1.
CC -!- INTERACTION:
CC O43156:TTI1; NbExp=2; IntAct=EBI-968983, EBI-1055680;
CC -!- SUBCELLULAR LOCATION: Nucleus. Nucleus, PML body (By similarity).
CC Chromosome (By similarity). Note=Depending on the cell type, it
CC can also be found in PML nuclear bodies. Recruited to chromatin
CC during S-phase. Redistributes to discrete nuclear foci upon DNA
CC damage, hypoxia or replication fork stalling.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=1;
CC IsoId=Q13535-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q13535-2; Sequence=VSP_013305, VSP_013304;
CC Name=3;
CC IsoId=Q13535-3; Sequence=VSP_036907, VSP_036908;
CC Note=No experimental confirmation available;
CC -!- TISSUE SPECIFICITY: Ubiquitous, with highest expression in testis.
CC Isoform 2 is found in pancreas, placenta and liver but not in
CC heart, testis and ovary.
CC -!- PTM: Phosphorylated; autophosphorylates in vitro.
CC -!- DISEASE: Seckel syndrome 1 (SCKL1) [MIM:210600]: A rare autosomal
CC recessive disorder characterized by proportionate dwarfism of
CC prenatal onset associated with low birth weight, growth
CC retardation, severe microcephaly with a bird-headed like
CC appearance, and mental retardation. Note=The disease is caused by
CC mutations affecting the gene represented in this entry.
CC -!- DISEASE: Cutaneous telangiectasia and cancer syndrome, familial
CC (FCTCS) [MIM:614564]: A disease characterized by cutaneous
CC telangiectases in infancy with patchy alopecia over areas of
CC affected skin, thinning of the lateral eyebrows, and mild dental
CC and nail anomalies. Affected individuals are at increased risk of
CC developing oropharyngeal cancer, and other malignancies have been
CC reported as well. Note=The disease is caused by mutations
CC affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the PI3/PI4-kinase family. ATM subfamily.
CC -!- SIMILARITY: Contains 1 FAT domain.
CC -!- SIMILARITY: Contains 1 FATC domain.
CC -!- SIMILARITY: Contains 2 HEAT repeats.
CC -!- SIMILARITY: Contains 1 PI3K/PI4K domain.
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/ATR";
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DR EMBL; Y09077; CAA70298.1; -; mRNA.
DR EMBL; U76308; AAC50929.1; -; mRNA.
DR EMBL; U49844; AAC50405.1; -; mRNA.
DR EMBL; AF325699; AAK26749.1; -; Genomic_DNA.
DR EMBL; AB208847; BAD92084.1; -; mRNA.
DR IPI; IPI00412298; -.
DR IPI; IPI00554573; -.
DR IPI; IPI00926461; -.
DR RefSeq; NP_001175.2; NM_001184.3.
DR UniGene; Hs.271791; -.
DR ProteinModelPortal; Q13535; -.
DR DIP; DIP-35308N; -.
DR IntAct; Q13535; 10.
DR MINT; MINT-194575; -.
DR STRING; 9606.ENSP00000343741; -.
DR PhosphoSite; Q13535; -.
DR DMDM; 62286460; -.
DR PaxDb; Q13535; -.
DR PRIDE; Q13535; -.
DR DNASU; 545; -.
DR Ensembl; ENST00000350721; ENSP00000343741; ENSG00000175054.
DR Ensembl; ENST00000383101; ENSP00000372581; ENSG00000175054.
DR GeneID; 545; -.
DR KEGG; hsa:545; -.
DR UCSC; uc003eux.4; human.
DR CTD; 545; -.
DR GeneCards; GC03M142168; -.
DR H-InvDB; HIX0030886; -.
DR HGNC; HGNC:882; ATR.
DR HPA; HPA028264; -.
DR MIM; 210600; phenotype.
DR MIM; 601215; gene.
DR MIM; 614564; phenotype.
DR neXtProt; NX_Q13535; -.
DR Orphanet; 808; Seckel syndrome.
DR PharmGKB; PA74; -.
DR eggNOG; COG5032; -.
DR HOGENOM; HOG000034221; -.
DR HOVERGEN; HBG050619; -.
DR InParanoid; Q13535; -.
DR KO; K06640; -.
DR OMA; AIQHENV; -.
DR OrthoDB; EOG48GW2C; -.
DR PhylomeDB; Q13535; -.
DR Pathway_Interaction_DB; bard1pathway; BARD1 signaling events.
DR Pathway_Interaction_DB; circadianpathway; Circadian rhythm pathway.
DR Reactome; REACT_111183; Meiosis.
DR Reactome; REACT_115566; Cell Cycle.
DR Reactome; REACT_216; DNA Repair.
DR BindingDB; Q13535; -.
DR ChEMBL; CHEMBL5024; -.
DR ChiTaRS; ATR; human.
DR GenomeRNAi; 545; -.
DR NextBio; 2253; -.
DR ArrayExpress; Q13535; -.
DR Bgee; Q13535; -.
DR CleanEx; HS_ATR; -.
DR Genevestigator; Q13535; -.
DR GermOnline; ENSG00000175054; Homo sapiens.
DR GO; GO:0005694; C:chromosome; ISS:UniProtKB.
DR GO; GO:0005654; C:nucleoplasm; TAS:Reactome.
DR GO; GO:0016605; C:PML body; IEA:UniProtKB-SubCell.
DR GO; GO:0001741; C:XY body; IEA:Compara.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0003677; F:DNA binding; IEA:UniProtKB-KW.
DR GO; GO:0032405; F:MutLalpha complex binding; IDA:MGI.
DR GO; GO:0032407; F:MutSalpha complex binding; IDA:MGI.
DR GO; GO:0004674; F:protein serine/threonine kinase activity; IDA:BHF-UCL.
DR GO; GO:0071480; P:cellular response to gamma radiation; IDA:BHF-UCL.
DR GO; GO:0034644; P:cellular response to UV; IMP:BHF-UCL.
DR GO; GO:0000077; P:DNA damage checkpoint; IDA:UniProtKB.
DR GO; GO:0006281; P:DNA repair; TAS:Reactome.
DR GO; GO:0006260; P:DNA replication; TAS:Reactome.
DR GO; GO:0007275; P:multicellular organismal development; TAS:ProtInc.
DR GO; GO:0008156; P:negative regulation of DNA replication; IMP:UniProtKB.
DR GO; GO:0018105; P:peptidyl-serine phosphorylation; IDA:BHF-UCL.
DR GO; GO:0043517; P:positive regulation of DNA damage response, signal transduction by p53 class mediator; IMP:BHF-UCL.
DR GO; GO:0046777; P:protein autophosphorylation; IDA:BHF-UCL.
DR GO; GO:0043393; P:regulation of protein binding; IEA:Compara.
DR GO; GO:0090399; P:replicative senescence; IMP:BHF-UCL.
DR Gene3D; 1.10.1070.11; -; 2.
DR Gene3D; 1.25.10.10; -; 4.
DR Gene3D; 1.25.40.10; -; 3.
DR InterPro; IPR011989; ARM-like.
DR InterPro; IPR016024; ARM-type_fold.
DR InterPro; IPR003152; FATC.
DR InterPro; IPR021133; HEAT_type_2.
DR InterPro; IPR011009; Kinase-like_dom.
DR InterPro; IPR000403; PI3/4_kinase_cat_dom.
DR InterPro; IPR018936; PI3/4_kinase_CS.
DR InterPro; IPR003151; PIK-rel_kinase_FAT.
DR InterPro; IPR014009; PIK_FAT.
DR InterPro; IPR011990; TPR-like_helical.
DR InterPro; IPR012993; UME.
DR Pfam; PF02259; FAT; 1.
DR Pfam; PF02260; FATC; 1.
DR Pfam; PF00454; PI3_PI4_kinase; 1.
DR Pfam; PF08064; UME; 1.
DR SMART; SM00146; PI3Kc; 1.
DR SMART; SM00802; UME; 1.
DR SUPFAM; SSF48371; ARM-type_fold; 1.
DR SUPFAM; SSF56112; Kinase_like; 1.
DR PROSITE; PS51189; FAT; 1.
DR PROSITE; PS51190; FATC; 1.
DR PROSITE; PS50077; HEAT_REPEAT; 1.
DR PROSITE; PS00915; PI3_4_KINASE_1; FALSE_NEG.
DR PROSITE; PS00916; PI3_4_KINASE_2; 1.
DR PROSITE; PS50290; PI3_4_KINASE_3; 1.
PE 1: Evidence at protein level;
KW Alternative splicing; ATP-binding; Chromosome; Complete proteome;
KW Disease mutation; DNA damage; DNA repair; DNA-binding; Dwarfism;
KW Kinase; Manganese; Mental retardation; Nucleotide-binding; Nucleus;
KW Phosphoprotein; Polymorphism; Reference proteome; Repeat;
KW Serine/threonine-protein kinase; Transferase.
FT CHAIN 1 2644 Serine/threonine-protein kinase ATR.
FT /FTId=PRO_0000088844.
FT REPEAT 799 835 HEAT 1.
FT REPEAT 1329 1365 HEAT 2.
FT DOMAIN 1640 2185 FAT.
FT DOMAIN 2322 2567 PI3K/PI4K.
FT DOMAIN 2612 2644 FATC.
FT MOD_RES 428 428 Phosphoserine.
FT MOD_RES 1989 1989 Phosphothreonine.
FT VAR_SEQ 450 450 E -> D (in isoform 2).
FT /FTId=VSP_013305.
FT VAR_SEQ 451 514 Missing (in isoform 2).
FT /FTId=VSP_013304.
FT VAR_SEQ 2588 2610 AKTHVLDIEQRLQGVIKTRNRVT -> VSRRYSLIWAVVLI
FT STNELDMQL (in isoform 3).
FT /FTId=VSP_036907.
FT VAR_SEQ 2611 2644 Missing (in isoform 3).
FT /FTId=VSP_036908.
FT VARIANT 64 64 T -> A (in dbSNP:rs35306038).
FT /FTId=VAR_041584.
FT VARIANT 90 90 H -> Y (in dbSNP:rs28897763).
FT /FTId=VAR_041585.
FT VARIANT 211 211 M -> T (in dbSNP:rs2227928).
FT /FTId=VAR_050532.
FT VARIANT 297 297 K -> N (in dbSNP:rs2229033).
FT /FTId=VAR_041586.
FT VARIANT 316 316 V -> I (in dbSNP:rs28897764).
FT /FTId=VAR_041587.
FT VARIANT 959 959 V -> M (in dbSNP:rs28910271).
FT /FTId=VAR_041588.
FT VARIANT 1087 1087 Y -> H (in dbSNP:rs34253059).
FT /FTId=VAR_041589.
FT VARIANT 1213 1213 S -> G (in dbSNP:rs34766606).
FT /FTId=VAR_041590.
FT VARIANT 1488 1488 A -> P (in a lung squamous cell carcinoma
FT sample; somatic mutation).
FT /FTId=VAR_041591.
FT VARIANT 1526 1526 I -> V (in dbSNP:rs34124242).
FT /FTId=VAR_050533.
FT VARIANT 1607 1607 S -> N (in dbSNP:rs55724025).
FT /FTId=VAR_041592.
FT VARIANT 1612 1612 N -> S (in dbSNP:rs55894265).
FT /FTId=VAR_041593.
FT VARIANT 2002 2002 A -> G (in a lung adenocarcinoma sample;
FT somatic mutation).
FT /FTId=VAR_041594.
FT VARIANT 2120 2120 G -> A (in dbSNP:rs35134774).
FT /FTId=VAR_041595.
FT VARIANT 2132 2132 Y -> D (in dbSNP:rs28910273).
FT /FTId=VAR_041596.
FT VARIANT 2144 2144 Q -> R (in FCTCS).
FT /FTId=VAR_067919.
FT VARIANT 2233 2233 S -> I (in a lung large cell carcinoma
FT sample; somatic mutation).
FT /FTId=VAR_041597.
FT VARIANT 2425 2425 R -> Q (in dbSNP:rs2229032).
FT /FTId=VAR_041598.
FT VARIANT 2434 2434 P -> A (in dbSNP:rs33972295).
FT /FTId=VAR_041599.
FT VARIANT 2438 2438 E -> K (in a breast pleomorphic lobular
FT carcinoma sample; somatic mutation).
FT /FTId=VAR_041600.
FT VARIANT 2537 2537 E -> Q (in a breast infiltrating ductal
FT carcinoma sample; somatic mutation).
FT /FTId=VAR_041601.
FT MUTAGEN 2327 2327 K->R: Abolishes kinase activity.
FT MUTAGEN 2475 2475 D->A: Abolishes kinase activity;
FT increases sensitivity to IR and impairs
FT translocation to nuclear foci upon DNA
FT damage.
FT MUTAGEN 2494 2494 D->E: Abolishes kinase activity; reduces
FT cell viability, augments sensitivity to
FT IR and UV.
FT CONFLICT 92 92 A -> R (in Ref. 1; CAA70298/AAC50929).
SQ SEQUENCE 2644 AA; 301367 MW; 11BC22297FB9A802 CRC64;
MGEHGLELAS MIPALRELGS ATPEEYNTVV QKPRQILCQF IDRILTDVNV VAVELVKKTD
SQPTSVMLLD FIQHIMKSSP LMFVNVSGSH EAKGSCIEFS NWIITRLLRI AATPSCHLLH
KKICEVICSL LFLFKSKSPA IFGVLTKELL QLFEDLVYLH RRNVMGHAVE WPVVMSRFLS
QLDEHMGYLQ SAPLQLMSMQ NLEFIEVTLL MVLTRIIAIV FFRRQELLLW QIGCVLLEYG
SPKIKSLAIS FLTELFQLGG LPAQPASTFF SSFLELLKHL VEMDTDQLKL YEEPLSKLIK
TLFPFEAEAY RNIEPVYLNM LLEKLCVMFE DGVLMRLKSD LLKAALCHLL QYFLKFVPAG
YESALQVRKV YVRNICKALL DVLGIEVDAE YLLGPLYAAL KMESMEIIEE IQCQTQQENL
SSNSDGISPK RRRLSSSLNP SKRAPKQTEE IKHVDMNQKS ILWSALKQKA ESLQISLEYS
GLKNPVIEML EGIAVVLQLT ALCTVHCSHQ NMNCRTFKDC QHKSKKKPSV VITWMSLDFY
TKVLKSCRSL LESVQKLDLE ATIDKVVKIY DALIYMQVNS SFEDHILEDL CGMLSLPWIY
SHSDDGCLKL TTFAANLLTL SCRISDSYSP QAQSRCVFLL TLFPRRIFLE WRTAVYNWAL
QSSHEVIRAS CVSGFFILLQ QQNSCNRVPK ILIDKVKDDS DIVKKEFASI LGQLVCTLHG
MFYLTSSLTE PFSEHGHVDL FCRNLKATSQ HECSSSQLKA SVCKPFLFLL KKKIPSPVKL
AFIDNLHHLC KHLDFREDET DVKAVLGTLL NLMEDPDKDV RVAFSGNIKH ILESLDSEDG
FIKELFVLRM KEAYTHAQIS RNNELKDTLI LTTGDIGRAA KGDLVPFALL HLLHCLLSKS
ASVSGAAYTE IRALVAAKSV KLQSFFSQYK KPICQFLVES LHSSQMTALP NTPCQNADVR
KQDVAHQREM ALNTLSEIAN VFDFPDLNRF LTRTLQVLLP DLAAKASPAA SALIRTLGKQ
LNVNRREILI NNFKYIFSHL VCSCSKDELE RALHYLKNET EIELGSLLRQ DFQGLHNELL
LRIGEHYQQV FNGLSILASF ASSDDPYQGP RDIISPELMA DYLQPKLLGI LAFFNMQLLS
SSVGIEDKKM ALNSLMSLMK LMGPKHVSSV RVKMMTTLRT GLRFKDDFPE LCCRAWDCFV
RCLDHACLGS LLSHVIVALL PLIHIQPKET AAIFHYLIIE NRDAVQDFLH EIYFLPDHPE
LKKIKAVLQE YRKETSESTD LQTTLQLSMK AIQHENVDVR IHALTSLKET LYKNQEKLIK
YATDSETVEP IISQLVTVLL KGCQDANSQA RLLCGECLGE LGAIDPGRLD FSTTETQGKD
FTFVTGVEDS SFAYGLLMEL TRAYLAYADN SRAQDSAAYA IQELLSIYDC REMETNGPGH
QLWRRFPEHV REILEPHLNT RYKSSQKSTD WSGVKKPIYL SKLGSNFAEW SASWAGYLIT
KVRHDLASKI FTCCSIMMKH DFKVTIYLLP HILVYVLLGC NQEDQQEVYA EIMAVLKHDD
QHTINTQDIA SDLCQLSTQT VFSMLDHLTQ WARHKFQALK AEKCPHSKSN RNKVDSMVST
VDYEDYQSVT RFLDLIPQDT LAVASFRSKA YTRAVMHFES FITEKKQNIQ EHLGFLQKLY
AAMHEPDGVA GVSAIRKAEP SLKEQILEHE SLGLLRDATA CYDRAIQLEP DQIIHYHGVV
KSMLGLGQLS TVITQVNGVH ANRSEWTDEL NTYRVEAAWK LSQWDLVENY LAADGKSTTW
SVRLGQLLLS AKKRDITAFY DSLKLVRAEQ IVPLSAASFE RGSYQRGYEY IVRLHMLCEL
EHSIKPLFQH SPGDSSQEDS LNWVARLEMT QNSYRAKEPI LALRRALLSL NKRPDYNEMV
GECWLQSARV ARKAGHHQTA YNALLNAGES RLAELYVERA KWLWSKGDVH QALIVLQKGV
ELCFPENETP PEGKNMLIHG RAMLLVGRFM EETANFESNA IMKKYKDVTA CLPEWEDGHF
YLAKYYDKLM PMVTDNKMEK QGDLIRYIVL HFGRSLQYGN QFIYQSMPRM LTLWLDYGTK
AYEWEKAGRS DRVQMRNDLG KINKVITEHT NYLAPYQFLT AFSQLISRIC HSHDEVFVVL
MEIIAKVFLA YPQQAMWMMT AVSKSSYPMR VNRCKEILNK AIHMKKSLEK FVGDATRLTD
KLLELCNKPV DGSSSTLSMS THFKMLKKLV EEATFSEILI PLQSVMIPTL PSILGTHANH
ASHEPFPGHW AYIAGFDDMV EILASLQKPK KISLKGSDGK FYIMMCKPKD DLRKDCRLME
FNSLINKCLR KDAESRRREL HIRTYAVIPL NDECGIIEWV NNTAGLRPIL TKLYKEKGVY
MTGKELRQCM LPKSAALSEK LKVFREFLLP RHPPIFHEWF LRTFPDPTSW YSSRSAYCRS
TAVMSMVGYI LGLGDRHGEN ILFDSLTGEC VHVDFNCLFN KGETFEVPEI VPFRLTHNMV
NGMGPMGTEG LFRRACEVTM RLMRDQREPL MSVLKTFLHD PLVEWSKPVK GHSKAPLNET
GEVVNEKAKT HVLDIEQRLQ GVIKTRNRVT GLPLSIEGHV HYLIQEATDE NLLCQMYLGW
TPYM
//
