ATR_HUMAN
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 03-AUG-2022, entry version 202.
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; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RX PubMed=8978690; DOI=10.1002/j.1460-2075.1996.tb01054.x;
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 checkpoint
RT 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 2), AND
RP 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., Adamson A.W.,
RA Den Z., Batzer M.A., Collins C.C., Brown K.D.;
RT "Evidence for alternate splicing within the mRNA transcript encoding the
RT 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., Brainerd E.E.,
RA Flaggs G., Bentley N.J., Taylor E.M., Meyn M.S., Moss S.B., Carr A.M.,
RA 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 ACTIVITY 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 DNA-
RT 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 HDAC2
RP 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 nucleosome
RT 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., Cliby W.A.,
RA 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 ATM
RT kinase family members.";
RL J. Biol. Chem. 274:37538-37543(1999).
RN [12]
RP FUNCTION, AUTOPHOSPHORYLATION, MUTAGENESIS OF ASP-2494, AND ACTIVITY
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 substrate
RT 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., Luo G.,
RA Carattini-Rivera S., DeMayo F., Bradley A., Donehower L.A., Elledge S.J.;
RT "Chk1 is an essential kinase that is regulated by Atr and required for the
RT 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 during
RT 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 to
RT 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., Ali A.,
RA Chen S.M., Abraham R.T., Wang X.-F.;
RT "ATR/ATM-mediated phosphorylation of human Rad17 is required for genotoxic
RT 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 and
RT 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 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 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 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 intra-S
RT 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) activation
RT 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 during S-
RT 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 the
RT 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 ACTIVITY 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 protein A
RT 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 ATR
RT 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 DNA
RT damage.";
RL Nature 434:605-611(2005).
RN [34]
RP ACTIVITY REGULATION.
RX PubMed=16530042; DOI=10.1016/j.cell.2005.12.041;
RA Kumagai A., Lee J., Yoo H.Y., Dunphy W.G.;
RT "TopBP1 activates the ATR-ATRIP complex.";
RL Cell 124:943-955(2006).
RN [35]
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 [36]
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 [37]
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., Wang X.F.;
RT "Protein phosphatase 5 is required for ATR-mediated checkpoint
RT activation.";
RL Mol. Cell. Biol. 25:9910-9919(2005).
RN [38]
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 the
RT kinome across the cell cycle.";
RL Mol. Cell 31:438-448(2008).
RN [39]
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 [40]
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., Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in a
RT refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [41]
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 damage
RT signaling and ATM and ATR stability.";
RL Genes Dev. 24:1939-1950(2010).
RN [42]
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 and
RT ATR complexes.";
RL Genes Dev. 24:2019-2030(2010).
RN [43]
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 [44]
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., Buerckstuemmer T.,
RA 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 [45]
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., Jun J.Y.,
RA You H.J.;
RT "Protein phosphatase 5 is necessary for ATR-mediated DNA repair.";
RL Biochem. Biophys. Res. Commun. 404:476-481(2011).
RN [46]
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., Johansen P.T.,
RA Kratchmarova I., Kassem M., Mann M., Olsen J.V., Blagoev B.;
RT "System-wide temporal characterization of the proteome and phosphoproteome
RT of human embryonic stem cell differentiation.";
RL Sci. Signal. 4:RS3-RS3(2011).
RN [47]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-435; SER-436 AND THR-1989,
RP AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma, and Erythroleukemia;
RX PubMed=23186163; DOI=10.1021/pr300630k;
RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J.,
RA Mohammed S.;
RT "Toward a comprehensive characterization of a human cancer cell
RT phosphoproteome.";
RL J. Proteome Res. 12:260-271(2013).
RN [48]
RP FUNCTION, ACTIVITY REGULATION, AND INTERACTION WITH ETAA1.
RX PubMed=27723720; DOI=10.1038/ncb3415;
RA Bass T.E., Luzwick J.W., Kavanaugh G., Carroll C., Dungrawala H.,
RA Glick G.G., Feldkamp M.D., Putney R., Chazin W.J., Cortez D.;
RT "ETAA1 acts at stalled replication forks to maintain genome integrity.";
RL Nat. Cell Biol. 18:1185-1195(2016).
RN [49]
RP FUNCTION, ACTIVITY REGULATION, AND INTERACTION WITH ETAA1.
RX PubMed=27723717; DOI=10.1038/ncb3422;
RA Haahr P., Hoffmann S., Tollenaere M.A., Ho T., Toledo L.I., Mann M.,
RA Bekker-Jensen S., Raeschle M., Mailand N.;
RT "Activation of the ATR kinase by the RPA-binding protein ETAA1.";
RL Nat. Cell Biol. 18:1196-1207(2016).
RN [50]
RP FUNCTION, AND INTERACTION WITH UHRF2.
RX PubMed=33848395; DOI=10.1111/gtc.12851;
RA Hanaki S., Habara M., Shimada M.;
RT "UV-induced activation of ATR is mediated by UHRF2.";
RL Genes Cells 26:447-454(2021).
RN [51]
RP VARIANTS [LARGE SCALE ANALYSIS] ALA-64; TYR-90; ASN-297; ILE-316; MET-959;
RP HIS-1087; GLY-1213; PRO-1488; ASN-1607; SER-1612; GLY-2002; ALA-2120;
RP ASP-2132; ILE-2233; GLN-2425; ALA-2434; LYS-2438 AND GLN-2537.
RX PubMed=17344846; DOI=10.1038/nature05610;
RA Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C., Bignell G.,
RA Davies H., Teague J., Butler A., Stevens C., Edkins S., O'Meara S.,
RA Vastrik I., Schmidt E.E., Avis T., Barthorpe S., Bhamra G., Buck G.,
RA Choudhury B., Clements J., Cole J., Dicks E., Forbes S., Gray K.,
RA Halliday K., Harrison R., Hills K., Hinton J., Jenkinson A., Jones D.,
RA Menzies A., Mironenko T., Perry J., Raine K., Richardson D., Shepherd R.,
RA Small A., Tofts C., Varian J., Webb T., West S., Widaa S., Yates A.,
RA Cahill D.P., Louis D.N., Goldstraw P., Nicholson A.G., Brasseur F.,
RA Looijenga L., Weber B.L., Chiew Y.-E., DeFazio A., Greaves M.F.,
RA Green A.R., Campbell P., Birney E., Easton D.F., Chenevix-Trench G.,
RA Tan M.-H., Khoo S.K., Teh B.T., Yuen S.T., Leung S.Y., Wooster R.,
RA Futreal P.A., Stratton M.R.;
RT "Patterns of somatic mutation in human cancer genomes.";
RL Nature 446:153-158(2007).
RN [52]
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 checkpoint
CC signaling upon genotoxic stresses such as ionizing radiation (IR),
CC ultraviolet light (UV), or DNA replication stalling, thereby acting as
CC a DNA damage sensor. Recognizes the substrate consensus sequence [ST]-
CC Q. Phosphorylates BRCA1, CHEK1, MCM2, RAD17, RPA2, SMC1 and p53/TP53,
CC which collectively inhibit DNA replication and mitosis and promote DNA
CC repair, recombination and apoptosis. Phosphorylates 'Ser-139' of
CC histone variant H2AX at sites of DNA damage, thereby regulating DNA
CC damage response mechanism. Required for FANCD2 ubiquitination. Critical
CC for maintenance of fragile site stability and efficient regulation of
CC centrosome duplication. Positively regulates the restart of stalled
CC replication forks following activation by the KHDC3L-OOEP scaffold
CC complex (By similarity). {ECO:0000250|UniProtKB:Q9JKK8,
CC ECO:0000269|PubMed:10597277, ECO:0000269|PubMed:10608806,
CC ECO:0000269|PubMed:10859164, ECO:0000269|PubMed:11114888,
CC ECO:0000269|PubMed:11418864, ECO:0000269|PubMed:11673449,
CC ECO:0000269|PubMed:11721054, ECO:0000269|PubMed:11865061,
CC ECO:0000269|PubMed:12526805, ECO:0000269|PubMed:12791985,
CC ECO:0000269|PubMed:12814551, ECO:0000269|PubMed:14657349,
CC ECO:0000269|PubMed:14729973, ECO:0000269|PubMed:14742437,
CC ECO:0000269|PubMed:15210935, ECO:0000269|PubMed:15314022,
CC ECO:0000269|PubMed:15496423, ECO:0000269|PubMed:16260606,
CC ECO:0000269|PubMed:21144835, ECO:0000269|PubMed:27723717,
CC ECO:0000269|PubMed:27723720, ECO:0000269|PubMed:33848395,
CC ECO:0000269|PubMed:9427750, ECO:0000269|PubMed:9636169,
CC ECO:0000269|PubMed:9925639}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + L-seryl-[protein] = ADP + H(+) + O-phospho-L-seryl-
CC [protein]; Xref=Rhea:RHEA:17989, Rhea:RHEA-COMP:9863, Rhea:RHEA-
CC COMP:11604, ChEBI:CHEBI:15378, ChEBI:CHEBI:29999, ChEBI:CHEBI:30616,
CC ChEBI:CHEBI:83421, ChEBI:CHEBI:456216; EC=2.7.11.1;
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + L-threonyl-[protein] = ADP + H(+) + O-phospho-L-
CC threonyl-[protein]; Xref=Rhea:RHEA:46608, Rhea:RHEA-COMP:11060,
CC Rhea:RHEA-COMP:11605, ChEBI:CHEBI:15378, ChEBI:CHEBI:30013,
CC ChEBI:CHEBI:30616, ChEBI:CHEBI:61977, ChEBI:CHEBI:456216;
CC EC=2.7.11.1;
CC -!- COFACTOR:
CC Name=Mn(2+); Xref=ChEBI:CHEBI:29035;
CC Evidence={ECO:0000269|PubMed:10608806};
CC -!- ACTIVITY REGULATION: Serine/threonine-protein kinase activity is
CC directly stimulated by TOPBP1 (PubMed:16530042). ATR kinase activity is
CC also directly activated by ETAA1, independently of TOPBP1
CC (PubMed:27723720, PubMed:27723717). Activated by DNA and inhibited by
CC BCR-ABL oncogene (PubMed:10597277). Slightly activated by ATRIP
CC (PubMed:14729973). Inhibited by caffeine, wortmannin and LY294002
CC (PubMed:9766667). {ECO:0000269|PubMed:10597277,
CC ECO:0000269|PubMed:14729973, ECO:0000269|PubMed:16530042,
CC ECO:0000269|PubMed:27723717, ECO:0000269|PubMed:27723720,
CC ECO:0000269|PubMed:9766667}.
CC -!- SUBUNIT: Forms a heterodimer with ATRIP.(PubMed:11721054). Binds to
CC DNA, and to UV-damaged DNA with higher affinity. Interacts with RAD17,
CC MSH2 and HDAC2. Present in a complex containing ATRIP and RPA-coated
CC single-stranded DNA. Present in a complex containing CHD4 and HDAC2.
CC Interacts with EEF1E1, the interaction is enhanced by UV irradiation.
CC Interacts with CLSPN and CEP164. Interacts with TELO2 and TTI1.
CC Interacts with BCR-ABL after genotoxic stress. Interacts with UHRF2;
CC this interaction promotes ATR activation. {ECO:0000250,
CC ECO:0000269|PubMed:10545197, ECO:0000269|PubMed:11418864,
CC ECO:0000269|PubMed:11721054, ECO:0000269|PubMed:12766152,
CC ECO:0000269|PubMed:12791985, ECO:0000269|PubMed:14657349,
CC ECO:0000269|PubMed:14729973, ECO:0000269|PubMed:15050919,
CC ECO:0000269|PubMed:15680327, ECO:0000269|PubMed:15758953,
CC ECO:0000269|PubMed:16260606, ECO:0000269|PubMed:18283122,
CC ECO:0000269|PubMed:20427287, ECO:0000269|PubMed:20801936,
CC ECO:0000269|PubMed:20810650, ECO:0000269|PubMed:33848395}.
CC -!- INTERACTION:
CC Q13535; Q8WXE1: ATRIP; NbExp=4; IntAct=EBI-968983, EBI-747353;
CC Q13535; Q99459: CDC5L; NbExp=3; IntAct=EBI-968983, EBI-374880;
CC Q13535; P50750: CDK9; NbExp=3; IntAct=EBI-968983, EBI-1383449;
CC Q13535; Q9BW66: CINP; NbExp=5; IntAct=EBI-968983, EBI-739784;
CC Q13535; Q9Y6K9: IKBKG; NbExp=2; IntAct=EBI-968983, EBI-81279;
CC Q13535; O43156: TTI1; NbExp=2; IntAct=EBI-968983, EBI-1055680;
CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:11114888,
CC ECO:0000269|PubMed:11721054, ECO:0000269|PubMed:11865061,
CC ECO:0000269|PubMed:12814551, ECO:0000269|PubMed:14871897,
CC ECO:0000269|PubMed:16260606, ECO:0000269|PubMed:18283122,
CC ECO:0000269|PubMed:8843195}. Chromosome {ECO:0000250|UniProtKB:Q9JKK8}.
CC Note=Depending on the cell type, it can also be found in PML nuclear
CC bodies. Recruited to chromatin during S-phase. Redistributes to
CC discrete nuclear foci upon DNA damage, hypoxia or replication fork
CC 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 -!- TISSUE SPECIFICITY: Ubiquitous, with highest expression in testis.
CC Isoform 2 is found in pancreas, placenta and liver but not in heart,
CC testis and ovary. {ECO:0000269|PubMed:11470508,
CC ECO:0000269|PubMed:8610130, ECO:0000269|PubMed:8843195}.
CC -!- PTM: Phosphorylated; autophosphorylates in vitro.
CC {ECO:0000269|PubMed:21144835}.
CC -!- DISEASE: Seckel syndrome 1 (SCKL1) [MIM:210600]: A rare autosomal
CC recessive disorder characterized by proportionate dwarfism of prenatal
CC onset associated with low birth weight, growth retardation, severe
CC microcephaly with a bird-headed like appearance, and intellectual
CC disability. {ECO:0000269|PubMed:12640452}. Note=The disease is caused
CC by variants affecting the gene represented in this entry.
CC -!- DISEASE: Cutaneous telangiectasia and cancer syndrome, familial (FCTCS)
CC [MIM:614564]: A disease characterized by cutaneous telangiectases in
CC infancy with patchy alopecia over areas of affected skin, thinning of
CC the lateral eyebrows, and mild dental and nail anomalies. Affected
CC individuals are at increased risk of developing oropharyngeal cancer,
CC and other malignancies have been reported as well.
CC {ECO:0000269|PubMed:22341969}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the PI3/PI4-kinase family. ATM subfamily.
CC {ECO:0000305}.
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and
CC Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/ATRID728ch3q23.html";
CC ---------------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution (CC BY 4.0) License
CC ---------------------------------------------------------------------------
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 RefSeq; XP_016862132.1; XM_017006643.1.
DR PDB; 5YZ0; EM; 4.70 A; A/B=1-2644.
DR PDBsum; 5YZ0; -.
DR AlphaFoldDB; Q13535; -.
DR SMR; Q13535; -.
DR BioGRID; 107027; 203.
DR ComplexPortal; CPX-3622; ATR-ATRIP DNA damage-sensing kinase complex.
DR CORUM; Q13535; -.
DR DIP; DIP-35308N; -.
DR IntAct; Q13535; 54.
DR MINT; Q13535; -.
DR STRING; 9606.ENSP00000343741; -.
DR BindingDB; Q13535; -.
DR ChEMBL; CHEMBL5024; -.
DR DrugBank; DB14917; Ceralasertib.
DR GuidetoPHARMACOLOGY; 1935; -.
DR CarbonylDB; Q13535; -.
DR iPTMnet; Q13535; -.
DR PhosphoSitePlus; Q13535; -.
DR BioMuta; ATR; -.
DR DMDM; 62286460; -.
DR CPTAC; CPTAC-3214; -.
DR CPTAC; CPTAC-3215; -.
DR EPD; Q13535; -.
DR jPOST; Q13535; -.
DR MassIVE; Q13535; -.
DR MaxQB; Q13535; -.
DR PaxDb; Q13535; -.
DR PeptideAtlas; Q13535; -.
DR PRIDE; Q13535; -.
DR ProteomicsDB; 59521; -. [Q13535-1]
DR ProteomicsDB; 59522; -. [Q13535-2]
DR ProteomicsDB; 59523; -. [Q13535-3]
DR Antibodypedia; 18078; 549 antibodies from 40 providers.
DR CPTC; Q13535; 1 antibody.
DR DNASU; 545; -.
DR Ensembl; ENST00000350721.9; ENSP00000343741.4; ENSG00000175054.16. [Q13535-1]
DR Ensembl; ENST00000661310.1; ENSP00000499589.1; ENSG00000175054.16. [Q13535-2]
DR GeneID; 545; -.
DR KEGG; hsa:545; -.
DR MANE-Select; ENST00000350721.9; ENSP00000343741.4; NM_001184.4; NP_001175.2.
DR UCSC; uc003eux.5; human. [Q13535-1]
DR CTD; 545; -.
DR DisGeNET; 545; -.
DR GeneCards; ATR; -.
DR HGNC; HGNC:882; ATR.
DR HPA; ENSG00000175054; Low tissue specificity.
DR MalaCards; ATR; -.
DR MIM; 210600; phenotype.
DR MIM; 601215; gene.
DR MIM; 614564; phenotype.
DR neXtProt; NX_Q13535; -.
DR OpenTargets; ENSG00000175054; -.
DR Orphanet; 313846; Familial cutaneous telangiectasia and oropharyngeal cancer predisposition syndrome.
DR Orphanet; 808; Seckel syndrome.
DR PharmGKB; PA74; -.
DR VEuPathDB; HostDB:ENSG00000175054; -.
DR eggNOG; KOG0890; Eukaryota.
DR GeneTree; ENSGT00940000155714; -.
DR HOGENOM; CLU_000178_2_1_1; -.
DR InParanoid; Q13535; -.
DR OMA; YTVYSQM; -.
DR OrthoDB; 80538at2759; -.
DR PhylomeDB; Q13535; -.
DR TreeFam; TF101183; -.
DR BRENDA; 2.7.11.1; 2681.
DR PathwayCommons; Q13535; -.
DR Reactome; R-HSA-1221632; Meiotic synapsis.
DR Reactome; R-HSA-176187; Activation of ATR in response to replication stress.
DR Reactome; R-HSA-3371453; Regulation of HSF1-mediated heat shock response.
DR Reactome; R-HSA-5685938; HDR through Single Strand Annealing (SSA).
DR Reactome; R-HSA-5693607; Processing of DNA double-strand break ends.
DR Reactome; R-HSA-5693616; Presynaptic phase of homologous DNA pairing and strand exchange.
DR Reactome; R-HSA-6783310; Fanconi Anemia Pathway.
DR Reactome; R-HSA-6796648; TP53 Regulates Transcription of DNA Repair Genes.
DR Reactome; R-HSA-6804756; Regulation of TP53 Activity through Phosphorylation.
DR Reactome; R-HSA-69473; G2/M DNA damage checkpoint.
DR Reactome; R-HSA-9709570; Impaired BRCA2 binding to RAD51.
DR SignaLink; Q13535; -.
DR SIGNOR; Q13535; -.
DR BioGRID-ORCS; 545; 717 hits in 1121 CRISPR screens.
DR ChiTaRS; ATR; human.
DR GeneWiki; Ataxia_telangiectasia_and_Rad3_related; -.
DR GenomeRNAi; 545; -.
DR Pharos; Q13535; Tchem.
DR PRO; PR:Q13535; -.
DR Proteomes; UP000005640; Chromosome 3.
DR RNAct; Q13535; protein.
DR Bgee; ENSG00000175054; Expressed in Brodmann (1909) area 23 and 203 other tissues.
DR ExpressionAtlas; Q13535; baseline and differential.
DR Genevisible; Q13535; HS.
DR GO; GO:0070310; C:ATR-ATRIP complex; IPI:ComplexPortal.
DR GO; GO:0005694; C:chromosome; ISS:UniProtKB.
DR GO; GO:0005794; C:Golgi apparatus; IDA:HPA.
DR GO; GO:0005654; C:nucleoplasm; IDA:HPA.
DR GO; GO:0005634; C:nucleus; IBA:GO_Central.
DR GO; GO:0016605; C:PML body; IDA:UniProtKB.
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:0004672; F:protein kinase activity; IDA:UniProtKB.
DR GO; GO:0106310; F:protein serine kinase activity; IEA:RHEA.
DR GO; GO:0004674; F:protein serine/threonine kinase activity; IDA:UniProtKB.
DR GO; GO:0006974; P:cellular response to DNA damage stimulus; IDA: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 signaling; IDA:UniProtKB.
DR GO; GO:0006281; P:DNA repair; TAS:ProtInc.
DR GO; GO:0006260; P:DNA replication; TAS:Reactome.
DR GO; GO:0097695; P:establishment of protein-containing complex localization to telomere; IC:BHF-UCL.
DR GO; GO:0097694; P:establishment of RNA localization to telomere; IMP:BHF-UCL.
DR GO; GO:0036297; P:interstrand cross-link repair; TAS:Reactome.
DR GO; GO:0008156; P:negative regulation of DNA replication; IMP:UniProtKB.
DR GO; GO:0006139; P:nucleobase-containing compound metabolic process; IC:ComplexPortal.
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:1904884; P:positive regulation of telomerase catalytic core complex assembly; IMP:BHF-UCL.
DR GO; GO:0032212; P:positive regulation of telomere maintenance via telomerase; ISS:BHF-UCL.
DR GO; GO:0046777; P:protein autophosphorylation; IDA:BHF-UCL.
DR GO; GO:0070198; P:protein localization to chromosome, telomeric region; IMP:BHF-UCL.
DR GO; GO:0006468; P:protein phosphorylation; IBA:GO_Central.
DR GO; GO:1900034; P:regulation of cellular response to heat; TAS:Reactome.
DR GO; GO:2000779; P:regulation of double-strand break repair; IC:ComplexPortal.
DR GO; GO:0031297; P:replication fork processing; ISS:UniProtKB.
DR GO; GO:0090399; P:replicative senescence; IMP:BHF-UCL.
DR GO; GO:0046685; P:response to arsenic-containing substance; IEA:Ensembl.
DR GO; GO:0009410; P:response to xenobiotic stimulus; IEA:Ensembl.
DR GO; GO:0000723; P:telomere maintenance; IBA:GO_Central.
DR Gene3D; 1.10.1070.11; -; 1.
DR Gene3D; 1.25.10.10; -; 2.
DR Gene3D; 1.25.40.10; -; 1.
DR InterPro; IPR011989; ARM-like.
DR InterPro; IPR016024; ARM-type_fold.
DR InterPro; IPR003152; FATC_dom.
DR InterPro; IPR021133; HEAT_type_2.
DR InterPro; IPR011009; Kinase-like_dom_sf.
DR InterPro; IPR000403; PI3/4_kinase_cat_dom.
DR InterPro; IPR036940; PI3/4_kinase_cat_sf.
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_dom_sf.
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; SM01343; FATC; 1.
DR SMART; SM00146; PI3Kc; 1.
DR SMART; SM00802; UME; 1.
DR SUPFAM; SSF48371; SSF48371; 2.
DR SUPFAM; SSF48452; SSF48452; 1.
DR SUPFAM; SSF56112; SSF56112; 1.
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 3D-structure; Alternative splicing; ATP-binding; Chromosome;
KW Disease variant; DNA damage; DNA repair; DNA-binding; Dwarfism;
KW Intellectual disability; Kinase; Manganese; Nucleotide-binding; Nucleus;
KW Phosphoprotein; Reference proteome; Repeat;
KW Serine/threonine-protein kinase; Transferase.
FT CHAIN 1..2644
FT /note="Serine/threonine-protein kinase ATR"
FT /id="PRO_0000088844"
FT REPEAT 799..835
FT /note="HEAT 1"
FT REPEAT 1329..1365
FT /note="HEAT 2"
FT DOMAIN 1640..2185
FT /note="FAT"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00534"
FT DOMAIN 2296..2604
FT /note="PI3K/PI4K catalytic"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00269"
FT DOMAIN 2612..2644
FT /note="FATC"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00534,
FT ECO:0000255|PROSITE-ProRule:PRU00535"
FT REGION 418..450
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 2302..2308
FT /note="G-loop"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00269"
FT REGION 2472..2480
FT /note="Catalytic loop"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00269"
FT REGION 2492..2516
FT /note="Activation loop"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00269"
FT COMPBIAS 418..444
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 428
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:21144835,
FT ECO:0007744|PubMed:18691976"
FT MOD_RES 435
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT MOD_RES 436
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT MOD_RES 1989
FT /note="Phosphothreonine"
FT /evidence="ECO:0007744|PubMed:18691976,
FT ECO:0007744|PubMed:23186163"
FT VAR_SEQ 450
FT /note="E -> D (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:11470508"
FT /id="VSP_013305"
FT VAR_SEQ 451..514
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:11470508"
FT /id="VSP_013304"
FT VAR_SEQ 2588..2610
FT /note="AKTHVLDIEQRLQGVIKTRNRVT -> VSRRYSLIWAVVLISTNELDMQL
FT (in isoform 3)"
FT /evidence="ECO:0000303|Ref.4"
FT /id="VSP_036907"
FT VAR_SEQ 2611..2644
FT /note="Missing (in isoform 3)"
FT /evidence="ECO:0000303|Ref.4"
FT /id="VSP_036908"
FT VARIANT 64
FT /note="T -> A (in dbSNP:rs35306038)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_041584"
FT VARIANT 90
FT /note="H -> Y (in dbSNP:rs28897763)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_041585"
FT VARIANT 211
FT /note="M -> T (in dbSNP:rs2227928)"
FT /id="VAR_050532"
FT VARIANT 297
FT /note="K -> N (in dbSNP:rs2229033)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_041586"
FT VARIANT 316
FT /note="V -> I (in dbSNP:rs28897764)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_041587"
FT VARIANT 959
FT /note="V -> M (in dbSNP:rs28910271)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_041588"
FT VARIANT 1087
FT /note="Y -> H (in dbSNP:rs34253059)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_041589"
FT VARIANT 1213
FT /note="S -> G (in dbSNP:rs34766606)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_041590"
FT VARIANT 1488
FT /note="A -> P (in a lung squamous cell carcinoma sample;
FT somatic mutation)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_041591"
FT VARIANT 1526
FT /note="I -> V (in dbSNP:rs34124242)"
FT /id="VAR_050533"
FT VARIANT 1607
FT /note="S -> N (in dbSNP:rs55724025)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_041592"
FT VARIANT 1612
FT /note="N -> S (in dbSNP:rs55894265)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_041593"
FT VARIANT 2002
FT /note="A -> G (in a lung adenocarcinoma sample; somatic
FT mutation)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_041594"
FT VARIANT 2120
FT /note="G -> A (in dbSNP:rs35134774)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_041595"
FT VARIANT 2132
FT /note="Y -> D (in dbSNP:rs28910273)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_041596"
FT VARIANT 2144
FT /note="Q -> R (in FCTCS; dbSNP:rs387906797)"
FT /evidence="ECO:0000269|PubMed:22341969"
FT /id="VAR_067919"
FT VARIANT 2233
FT /note="S -> I (in a lung large cell carcinoma sample;
FT somatic mutation)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_041597"
FT VARIANT 2425
FT /note="R -> Q (in dbSNP:rs2229032)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_041598"
FT VARIANT 2434
FT /note="P -> A (in dbSNP:rs33972295)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_041599"
FT VARIANT 2438
FT /note="E -> K (in a breast pleomorphic lobular carcinoma
FT sample; somatic mutation)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_041600"
FT VARIANT 2537
FT /note="E -> Q (in a breast infiltrating ductal carcinoma
FT sample; somatic mutation)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_041601"
FT MUTAGEN 2327
FT /note="K->R: Abolishes kinase activity."
FT /evidence="ECO:0000269|PubMed:11114888,
FT ECO:0000269|PubMed:12011431, ECO:0000269|PubMed:9925639"
FT MUTAGEN 2475
FT /note="D->A: Abolishes kinase activity; increases
FT sensitivity to IR and impairs translocation to nuclear foci
FT upon DNA damage."
FT /evidence="ECO:0000269|PubMed:12814551,
FT ECO:0000269|PubMed:9427750, ECO:0000269|PubMed:9925639"
FT MUTAGEN 2494
FT /note="D->E: Abolishes kinase activity; reduces cell
FT viability, augments sensitivity to IR and UV."
FT /evidence="ECO:0000269|PubMed:10597277,
FT ECO:0000269|PubMed:9636169"
FT CONFLICT 92
FT /note="A -> R (in Ref. 1; CAA70298/AAC50929)"
FT /evidence="ECO:0000305"
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
