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Database: UniProt
Entry: Q13535
LinkDB: Q13535
Original site: Q13535 
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   09-JUL-2014, entry version 136.
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; DOI=10.1101/gad.10.19.2423;
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; DOI=10.1101/gad.13.2.152;
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 IDENTIFICATION BY MASS
RP   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   FUNCTION IN DNA DAMAGE RESPONSE, INTERACTION WITH PPP5C,
RP   AUTOPHOSPHORYLATION, AND SUBCELLULAR LOCATION.
RX   PubMed=16260606; DOI=10.1128/MCB.25.22.9910-9919.2005;
RA   Zhang J., Bao S., Furumai R., Kucera K.S., Ali A., Dean N.M.,
RA   Wang X.F.;
RT   "Protein phosphatase 5 is required for ATR-mediated checkpoint
RT   activation.";
RL   Mol. Cell. Biol. 25:9910-9919(2005).
RN   [37]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-428 AND THR-1989, AND
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
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   [38]
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   [39]
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX   PubMed=19413330; DOI=10.1021/ac9004309;
RA   Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J.,
RA   Mohammed S.;
RT   "Lys-N and trypsin cover complementary parts of the phosphoproteome in
RT   a refined SCX-based approach.";
RL   Anal. Chem. 81:4493-4501(2009).
RN   [40]
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   [41]
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   [42]
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   [43]
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   [44]
RP   FUNCTION IN DNA REPAIR, AND PHOSPHORYLATION AT SER-428.
RX   PubMed=21144835; DOI=10.1016/j.bbrc.2010.12.005;
RA   Kang Y., Cheong H.M., Lee J.H., Song P.I., Lee K.H., Kim S.Y.,
RA   Jun J.Y., You H.J.;
RT   "Protein phosphatase 5 is necessary for ATR-mediated DNA repair.";
RL   Biochem. Biophys. Res. Commun. 404:476-481(2011).
RN   [45]
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   [46]
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   [47]
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       Q99459:CDC5L; NbExp=3; IntAct=EBI-968983, EBI-374880;
CC       P50750:CDK9; NbExp=3; IntAct=EBI-968983, EBI-1383449;
CC       Q9Y6K9:IKBKG; NbExp=2; IntAct=EBI-968983, EBI-81279;
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=Atlas of Genetics and Cytogenetics in Oncology
CC       and Haematology;
CC       URL="http://atlasgeneticsoncology.org/Genes/ATRID728ch3q23.html";
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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   CCDS; CCDS3124.1; -. [Q13535-1]
DR   RefSeq; NP_001175.2; NM_001184.3. [Q13535-1]
DR   UniGene; Hs.271791; -.
DR   ProteinModelPortal; Q13535; -.
DR   SMR; Q13535; 1647-2225, 2302-2544.
DR   BioGrid; 107027; 85.
DR   DIP; DIP-35308N; -.
DR   IntAct; Q13535; 15.
DR   MINT; MINT-194575; -.
DR   STRING; 9606.ENSP00000343741; -.
DR   BindingDB; Q13535; -.
DR   ChEMBL; CHEMBL5024; -.
DR   PhosphoSite; Q13535; -.
DR   DMDM; 62286460; -.
DR   MaxQB; Q13535; -.
DR   PaxDb; Q13535; -.
DR   PRIDE; Q13535; -.
DR   DNASU; 545; -.
DR   Ensembl; ENST00000350721; ENSP00000343741; ENSG00000175054. [Q13535-1]
DR   Ensembl; ENST00000383101; ENSP00000372581; ENSG00000175054. [Q13535-2]
DR   GeneID; 545; -.
DR   KEGG; hsa:545; -.
DR   UCSC; uc003eux.4; human. [Q13535-1]
DR   CTD; 545; -.
DR   GeneCards; GC03M142168; -.
DR   GeneReviews; ATR; -.
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; 313846; Familial cutaneous telangiectasia and oropharyngeal predisposition cancer syndrome.
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; EOG7Z95K8; -.
DR   PhylomeDB; Q13535; -.
DR   TreeFam; TF101183; -.
DR   Reactome; REACT_115566; Cell Cycle.
DR   Reactome; REACT_120956; Cellular responses to stress.
DR   Reactome; REACT_216; DNA Repair.
DR   SignaLink; Q13535; -.
DR   ChiTaRS; ATR; human.
DR   GeneWiki; Ataxia_telangiectasia_and_Rad3_related; -.
DR   GenomeRNAi; 545; -.
DR   NextBio; 2253; -.
DR   PRO; PR:Q13535; -.
DR   ArrayExpress; Q13535; -.
DR   Bgee; Q13535; -.
DR   CleanEx; HS_ATR; -.
DR   Genevestigator; Q13535; -.
DR   GO; GO:0005694; C:chromosome; ISS:UniProtKB.
DR   GO; GO:0005654; C:nucleoplasm; TAS:Reactome.
DR   GO; GO:0016605; C:PML body; IDA:UniProtKB.
DR   GO; GO:0001741; C:XY body; IEA:Ensembl.
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:0005515; F:protein binding; IPI:UniProtKB.
DR   GO; GO:0004672; F:protein kinase activity; IDA:UniProtKB.
DR   GO; GO:0004674; F:protein serine/threonine kinase activity; IDA:BHF-UCL.
DR   GO; GO:0007049; P:cell cycle; TAS:ProtInc.
DR   GO; GO:0006974; P:cellular response to DNA damage stimulus; TAS:UniProtKB.
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:Ensembl.
DR   GO; GO:0090399; P:replicative senescence; IMP:BHF-UCL.
DR   GO; GO:0042493; P:response to drug; IEA:Ensembl.
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; SSF48371; 7.
DR   SUPFAM; SSF56112; SSF56112; 2.
DR   PROSITE; PS51189; FAT; 1.
DR   PROSITE; PS51190; FATC; 1.
DR   PROSITE; PS50077; HEAT_REPEAT; 1.
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
//
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