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Database: UniProt
Entry: Q14191
LinkDB: Q14191
Original site: Q14191 
ID   WRN_HUMAN               Reviewed;        1432 AA.
AC   Q14191; A1KYY9;
DT   15-DEC-1998, integrated into UniProtKB/Swiss-Prot.
DT   08-FEB-2011, sequence version 2.
DT   16-OCT-2019, entry version 219.
DE   RecName: Full=Werner syndrome ATP-dependent helicase;
DE            EC=3.6.4.12 {ECO:0000269|PubMed:16622405};
DE   AltName: Full=DNA helicase, RecQ-like type 3;
DE            Short=RecQ3;
DE   AltName: Full=Exonuclease WRN;
DE            EC=3.1.-.-;
DE   AltName: Full=RecQ protein-like 2;
GN   Name=WRN; Synonyms=RECQ3, RECQL2;
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 [GENOMIC DNA], AND VARIANT PHE-1074.
RX   PubMed=8602509; DOI=10.1126/science.272.5259.258;
RA   Yu C.-E., Oshima J., Fu Y.-H., Wijsman E.M., Hisama F., Alisch R.,
RA   Matthews S., Nakura J., Miki T., Ouais S., Martin G.M., Mulligan J.,
RA   Schellenberg G.D.;
RT   "Positional cloning of the Werner's syndrome gene.";
RL   Science 272:258-262(1996).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [MRNA], AND VARIANT PHE-1074.
RX   PubMed=16723399; DOI=10.1073/pnas.0600645103;
RA   Agrelo R., Cheng W.H., Setien F., Ropero S., Espada J., Fraga M.F.,
RA   Herranz M., Paz M.F., Sanchez-Cespedes M., Artiga M.J., Guerrero D.,
RA   Castells A., von Kobbe C., Bohr V.A., Esteller M.;
RT   "Epigenetic inactivation of the premature aging Werner syndrome gene
RT   in human cancer.";
RL   Proc. Natl. Acad. Sci. U.S.A. 103:8822-8827(2006).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [MRNA], AND VARIANT PHE-1074.
RA   Paeper B.W., Gayle M., Brady W., Swartz A., Gillett L.A., Alisch R.S.,
RA   Mulligan J., Galas D., Fu Y.-H.;
RT   "Genomic structure of the human Werner's gene and cloning of the mouse
RT   homolog.";
RL   Submitted (AUG-1999) to the EMBL/GenBank/DDBJ databases.
RN   [4]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS ILE-114; LYS-343;
RP   ILE-387; SER-533; CYS-612; PHE-708; CYS-834; SER-912; LEU-1079;
RP   ALA-1133; ILE-1339 AND ARG-1367.
RG   NIEHS SNPs program;
RL   Submitted (OCT-2003) to the EMBL/GenBank/DDBJ databases.
RN   [5]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX   PubMed=16421571; DOI=10.1038/nature04406;
RA   Nusbaum C., Mikkelsen T.S., Zody M.C., Asakawa S., Taudien S.,
RA   Garber M., Kodira C.D., Schueler M.G., Shimizu A., Whittaker C.A.,
RA   Chang J.L., Cuomo C.A., Dewar K., FitzGerald M.G., Yang X.,
RA   Allen N.R., Anderson S., Asakawa T., Blechschmidt K., Bloom T.,
RA   Borowsky M.L., Butler J., Cook A., Corum B., DeArellano K.,
RA   DeCaprio D., Dooley K.T., Dorris L. III, Engels R., Gloeckner G.,
RA   Hafez N., Hagopian D.S., Hall J.L., Ishikawa S.K., Jaffe D.B.,
RA   Kamat A., Kudoh J., Lehmann R., Lokitsang T., Macdonald P.,
RA   Major J.E., Matthews C.D., Mauceli E., Menzel U., Mihalev A.H.,
RA   Minoshima S., Murayama Y., Naylor J.W., Nicol R., Nguyen C.,
RA   O'Leary S.B., O'Neill K., Parker S.C.J., Polley A., Raymond C.K.,
RA   Reichwald K., Rodriguez J., Sasaki T., Schilhabel M., Siddiqui R.,
RA   Smith C.L., Sneddon T.P., Talamas J.A., Tenzin P., Topham K.,
RA   Venkataraman V., Wen G., Yamazaki S., Young S.K., Zeng Q.,
RA   Zimmer A.R., Rosenthal A., Birren B.W., Platzer M., Shimizu N.,
RA   Lander E.S.;
RT   "DNA sequence and analysis of human chromosome 8.";
RL   Nature 439:331-335(2006).
RN   [6]
RP   SUBCELLULAR LOCATION.
RX   PubMed=9618508; DOI=10.1073/pnas.95.12.6887;
RA   Marciniak R.A., Lombard D.B., Johnson F.B., Guarente L.;
RT   "Nucleolar localization of the Werner syndrome protein in human
RT   cells.";
RL   Proc. Natl. Acad. Sci. U.S.A. 95:6887-6892(1998).
RN   [7]
RP   REPEATS.
RX   PubMed=10049920;
RA   Kusano K., Berres M.E., Engels W.R.;
RT   "Evolution of the RECQ family of helicases: a Drosophila homolog,
RT   Dmblm, is similar to the human Bloom syndrome gene.";
RL   Genetics 151:1027-1039(1999).
RN   [8]
RP   POSSIBLE INVOLVEMENT IN CRC.
RX   PubMed=9989816; DOI=10.1038/sj.onc.1202340;
RA   Chughtai S.A., Crundwell M.C., Cruickshank N.R., Affie E.,
RA   Armstrong S., Knowles M.A., Takle L.A., Kuo M., Khan N.,
RA   Phillips S.M., Neoptolemos J.P., Morton D.G.;
RT   "Two novel regions of interstitial deletion on chromosome 8p in
RT   colorectal cancer.";
RL   Oncogene 18:657-665(1999).
RN   [9]
RP   FUNCTION, MUTAGENESIS OF GLU-84, FUNCTION AS AN EXONUCLEASE,
RP   DNA-BINDING, INTERACTION WITH PCNA, AND SUBUNIT.
RX   PubMed=11863428; DOI=10.1021/bi0157161;
RA   Xue Y., Ratcliff G.C., Wang H., Davis-Searles P.R., Gray M.D.,
RA   Erie D.A., Redinbo M.R.;
RT   "A minimal exonuclease domain of WRN forms a hexamer on DNA and
RT   possesses both 3'- 5' exonuclease and 5'-protruding strand
RT   endonuclease activities.";
RL   Biochemistry 41:2901-2912(2002).
RN   [10]
RP   PHOSPHORYLATION.
RX   PubMed=11889123; DOI=10.1074/jbc.m111523200;
RA   Karmakar P., Piotrowski J., Brosh R.M. Jr., Sommers J.A., Miller S.P.,
RA   Cheng W.H., Snowden C.M., Ramsden D.A., Bohr V.A.;
RT   "Werner protein is a target of DNA-dependent protein kinase in vivo
RT   and in vitro, and its catalytic activities are regulated by
RT   phosphorylation.";
RL   J. Biol. Chem. 277:18291-18302(2002).
RN   [11]
RP   INTERACTION WITH EXO1.
RX   PubMed=12704184; DOI=10.1074/jbc.m212798200;
RA   Sharma S., Sommers J.A., Driscoll H.C., Uzdilla L.A., Wilson T.M.,
RA   Brosh R.M. Jr.;
RT   "The exonucleolytic and endonucleolytic cleavage activities of human
RT   exonuclease 1 are stimulated by an interaction with the carboxyl-
RT   terminal region of the Werner syndrome protein.";
RL   J. Biol. Chem. 278:23487-23496(2003).
RN   [12]
RP   INTERACTION WITH SUPV3L1.
RX   PubMed=17961633; DOI=10.1016/j.mad.2007.09.001;
RA   Pereira M., Mason P., Szczesny R.J., Maddukuri L., Dziwura S.,
RA   Jedrzejczak R., Paul E., Wojcik A., Dybczynska L., Tudek B.,
RA   Bartnik E., Klysik J., Bohr V.A., Stepien P.P.;
RT   "Interaction of human SUV3 RNA/DNA helicase with BLM helicase; loss of
RT   the SUV3 gene results in mouse embryonic lethality.";
RL   Mech. Ageing Dev. 128:609-617(2007).
RN   [13]
RP   FUNCTION, AND SUBCELLULAR LOCATION.
RX   PubMed=17563354; DOI=10.1073/pnas.0702513104;
RA   Kamath-Loeb A.S., Lan L., Nakajima S., Yasui A., Loeb L.A.;
RT   "Werner syndrome protein interacts functionally with translesion DNA
RT   polymerases.";
RL   Proc. Natl. Acad. Sci. U.S.A. 104:10394-10399(2007).
RN   [14]
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Embryonic kidney;
RX   PubMed=17525332; DOI=10.1126/science.1140321;
RA   Matsuoka S., Ballif B.A., Smogorzewska A., McDonald E.R. III,
RA   Hurov K.E., Luo J., Bakalarski C.E., Zhao Z., Solimini N.,
RA   Lerenthal Y., Shiloh Y., Gygi S.P., Elledge S.J.;
RT   "ATM and ATR substrate analysis reveals extensive protein networks
RT   responsive to DNA damage.";
RL   Science 316:1160-1166(2007).
RN   [15]
RP   FUNCTION, SUBUNIT, AND DNA-BINDING.
RX   PubMed=18596042; DOI=10.1074/jbc.m803370200;
RA   Compton S.A., Tolun G., Kamath-Loeb A.S., Loeb L.A., Griffith J.D.;
RT   "The Werner syndrome protein binds replication fork and Holliday
RT   junction DNAs as an oligomer.";
RL   J. Biol. Chem. 283:24478-24483(2008).
RN   [16]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-440 AND SER-467, AND
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   [17]
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   [18]
RP   FUNCTION, AND SUBCELLULAR LOCATION.
RX   PubMed=19652551; DOI=10.4161/cc.8.17.9410;
RA   Zecevic A., Menard H., Gurel V., Hagan E., DeCaro R., Zhitkovich A.;
RT   "WRN helicase promotes repair of DNA double-strand breaks caused by
RT   aberrant mismatch repair of chromium-DNA adducts.";
RL   Cell Cycle 8:2769-2778(2009).
RN   [19]
RP   FUNCTION.
RX   PubMed=19283071; DOI=10.1371/journal.pone.0004825;
RA   Opresko P.L., Sowd G., Wang H.;
RT   "The Werner syndrome helicase/exonuclease processes mobile D-loops
RT   through branch migration and degradation.";
RL   PLoS ONE 4:E4825-E4825(2009).
RN   [20]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-426; SER-440; SER-453
RP   AND SER-467, AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE
RP   ANALYSIS].
RC   TISSUE=Leukemic T-cell;
RX   PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA   Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA   Rodionov V., Han D.K.;
RT   "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT   reveals system-wide modulation of protein-protein interactions.";
RL   Sci. Signal. 2:RA46-RA46(2009).
RN   [21]
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   [22]
RP   FUNCTION, SUBCELLULAR LOCATION, AND INTERACTION WITH PML.
RX   PubMed=21639834; DOI=10.1134/s000629791105004x;
RA   Liu J., Song Y., Qian J., Liu B., Dong Y., Tian B., Sun Z.;
RT   "Promyelocytic leukemia protein interacts with werner syndrome
RT   helicase and regulates double-strand break repair in gamma-
RT   irradiation-induced DNA damage responses.";
RL   Biochemistry (Mosc.) 76:550-554(2011).
RN   [23]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1133, AND IDENTIFICATION
RP   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   [24]
RP   ACETYLATION [LARGE SCALE ANALYSIS] AT SER-2, CLEAVAGE OF INITIATOR
RP   METHIONINE [LARGE SCALE ANALYSIS], AND IDENTIFICATION BY MASS
RP   SPECTROMETRY [LARGE SCALE ANALYSIS].
RX   PubMed=22814378; DOI=10.1073/pnas.1210303109;
RA   Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A.,
RA   Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E.,
RA   Timmerman E., Prieto J., Arnesen T., Sherman F., Gevaert K.,
RA   Aldabe R.;
RT   "N-terminal acetylome analyses and functional insights of the N-
RT   terminal acetyltransferase NatB.";
RL   Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012).
RN   [25]
RP   POSSIBLE INVOLVEMENT IN CRC.
RX   PubMed=24308539; DOI=10.1186/1755-8794-6-54;
RA   Lee H., Flaherty P., Ji H.P.;
RT   "Systematic genomic identification of colorectal cancer genes
RT   delineating advanced from early clinical stage and metastasis.";
RL   BMC Med. Genomics 6:54-54(2013).
RN   [26]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-478; SER-1133 AND
RP   SER-1400, AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE
RP   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   [27]
RP   SUMOYLATION [LARGE SCALE ANALYSIS] AT LYS-154; LYS-241 AND LYS-252,
RP   AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX   PubMed=28112733; DOI=10.1038/nsmb.3366;
RA   Hendriks I.A., Lyon D., Young C., Jensen L.J., Vertegaal A.C.,
RA   Nielsen M.L.;
RT   "Site-specific mapping of the human SUMO proteome reveals co-
RT   modification with phosphorylation.";
RL   Nat. Struct. Mol. Biol. 24:325-336(2017).
RN   [28]
RP   STRUCTURE BY NMR OF 949-1092.
RX   PubMed=16339893; DOI=10.1073/pnas.0509380102;
RA   Hu J.S., Feng H., Zeng W., Lin G.X., Xi X.G.;
RT   "Solution structure of a multifunctional DNA- and protein-binding
RT   motif of human Werner syndrome protein.";
RL   Proc. Natl. Acad. Sci. U.S.A. 102:18379-18384(2005).
RN   [29]
RP   X-RAY CRYSTALLOGRAPHY (2.00 ANGSTROMS) OF 38-236 IN COMPLEXES WITH
RP   MAGNESIUM; MANGANESE; EUROPIUM AND GMP, PARTIAL PROTEIN SEQUENCE,
RP   IDENTIFICATION BY MASS SPECTROMETRY, CATALYTIC ACTIVITY, COFACTOR,
RP   MUTAGENESIS OF GLU-84; TRP-145 AND TYR-212, AND CHARACTERIZATION OF
RP   VARIANTS ILE-114 AND PRO-172.
RX   PubMed=16622405; DOI=10.1038/nsmb1088;
RA   Perry J.J., Yannone S.M., Holden L.G., Hitomi C., Asaithamby A.,
RA   Han S., Cooper P.K., Chen D.J., Tainer J.A.;
RT   "WRN exonuclease structure and molecular mechanism imply an editing
RT   role in DNA end processing.";
RL   Nat. Struct. Mol. Biol. 13:414-422(2006).
RN   [30]
RP   REVIEW ON VARIANTS.
RX   PubMed=10220139;
RX   DOI=10.1002/(sici)1098-1004(1999)13:4<271::aid-humu2>3.0.co;2-q;
RA   Moser M.J., Oshima J., Monnat R.J. Jr.;
RT   "WRN mutations in Werner syndrome.";
RL   Hum. Mutat. 13:271-279(1999).
RN   [31]
RP   STRUCTURE BY NMR OF 1140-1239.
RG   RIKEN structural genomics initiative (RSGI);
RT   "Solution structure of the helicase and RNase D C-terminal domain in
RT   Werner syndrome ATP-dependent helicase.";
RL   Submitted (SEP-2006) to the PDB data bank.
RN   [32]
RP   X-RAY CRYSTALLOGRAPHY (2.00 ANGSTROMS) OF 1142-1242, PARTIAL PROTEIN
RP   SEQUENCE, IDENTIFICATION BY MASS SPECTROMETRY, AND CIRCULAR DICHROISM.
RX   PubMed=17148451; DOI=10.1074/jbc.m610142200;
RA   Kitano K., Yoshihara N., Hakoshima T.;
RT   "Crystal structure of the HRDC domain of human Werner syndrome
RT   protein, WRN.";
RL   J. Biol. Chem. 282:2717-2728(2007).
RN   [33]
RP   X-RAY CRYSTALLOGRAPHY (1.90 ANGSTROMS) OF 949-1079 IN COMPLEX WITH
RP   DOUBLE-STRANDED DNA, INTERACTION WITH DNA, AND MUTAGENESIS OF ARG-987;
RP   SER-989; ARG-993; PHE-1037 AND MET-1038.
RX   PubMed=20159463; DOI=10.1016/j.str.2009.12.011;
RA   Kitano K., Kim S.Y., Hakoshima T.;
RT   "Structural basis for DNA strand separation by the unconventional
RT   winged-helix domain of RecQ helicase WRN.";
RL   Structure 18:177-187(2010).
RN   [34]
RP   VARIANT ARG-1367.
RX   PubMed=9021029;
RX   DOI=10.1002/(sici)1096-8628(19970211)68:4<494::aid-ajmg30>3.0.co;2-l;
RA   Ye L., Miki T., Nakura J., Oshima J., Kamino K., Rakugi H.,
RA   Ikegami H., Higaki J., Edland S.D., Martin G.M., Ogihara T.;
RT   "Association of a polymorphic variant of the Werner helicase gene with
RT   myocardial infarction in a Japanese population.";
RL   Am. J. Med. Genet. 68:494-498(1997).
RN   [35]
RP   ERRATUM.
RA   Ye L., Miki T., Nakura J., Oshima J., Kamino K., Rakugi H.,
RA   Ikegami H., Higaki J., Edland S.D., Martin G.M., Ogihara T.;
RL   Am. J. Med. Genet. 70:103-103(1997).
RN   [36]
RP   VARIANTS ILE-387 AND PHE-1074.
RX   PubMed=9450180;
RA   Meisslitzer C., Ruppitsch W., Weirich-Schwaiger H., Weirich H.G.,
RA   Jabkowsky J., Klein G., Schweiger M., Hirsch-Kauffmann M.;
RT   "Werner syndrome: characterization of mutations in the WRN gene in an
RT   affected family.";
RL   Eur. J. Hum. Genet. 5:364-370(1997).
RN   [37]
RP   VARIANT ILE-387.
RX   PubMed=10206685;
RX   DOI=10.1002/(sici)1098-1004(1998)11:5<413::aid-humu18>3.0.co;2-c;
RA   Vidal V., Bay J.-O., Champomier F., Grancho M., Beauville L.,
RA   Glowaczower C., Lemery D., Ferrara M., Bignon Y.-J.;
RT   "The 1396del A mutation and a missense mutation or a rare polymorphism
RT   of the WRN gene detected in a French Werner family with a severe
RT   phenotype and a case of an unusual vulvar cancer.";
RL   Hum. Mutat. 11:413-414(1998).
RN   [38]
RP   VARIANTS ALA-324 AND ARG-1367.
RX   PubMed=10069711;
RX   DOI=10.1002/(SICI)1096-8628(19990219)82:5<399::AID-AJMG8>3.3.CO;2-I;
RA   Castro E., Ogburn C.E., Hunt K.E., Tilvis R., Louhija J.,
RA   Penttinen R., Erkkola R., Panduro A., Riestra R., Piussan C.,
RA   Deeb S.S., Wang L., Edland S.D., Martin G.M., Oshima J.;
RT   "Polymorphisms at the Werner locus: I. Newly identified polymorphisms,
RT   ethnic variability of 1367Cys/Arg, and its stability in a population
RT   of Finnish centenarians.";
RL   Am. J. Med. Genet. 82:399-403(1999).
RN   [39]
RP   VARIANTS ARG-32; ILE-114; PRO-172; LYS-240; TRP-383; ILE-387; LEU-724;
RP   PHE-1074; GLU-1269 AND ARG-1367.
RX   PubMed=11161804; DOI=10.1006/geno.2000.6405;
RA   Passarino G., Shen P., Van Kirk J.B., Lin A.A., De Benedictis G.,
RA   Cavalli-Sforza L.L., Oefner P.J., Underhill P.A.;
RT   "The Werner syndrome gene and global sequence variation.";
RL   Genomics 71:118-122(2001).
RN   [40]
RP   VARIANTS WRN ASN-125 AND GLU-135.
RX   PubMed=16673358; DOI=10.1002/humu.20337;
RA   Huang S., Lee L., Hanson N.B., Lenaerts C., Hoehn H., Poot M.,
RA   Rubin C.D., Chen D.-F., Yang C.-C., Juch H., Dorn T., Spiegel R.,
RA   Oral E.A., Abid M., Battisti C., Lucci-Cordisco E., Neri G.,
RA   Steed E.H., Kidd A., Isley W., Showalter D., Vittone J.L.,
RA   Konstantinow A., Ring J., Meyer P., Wenger S.L., Herbay A.V.,
RA   Wollina U., Schuelke M., Huizenga C.R., Leistritz D.F., Martin G.M.,
RA   Mian I.S., Oshima J.;
RT   "The spectrum of WRN mutations in Werner syndrome patients.";
RL   Hum. Mutat. 27:558-567(2006).
RN   [41]
RP   VARIANT [LARGE SCALE ANALYSIS] VAL-92.
RX   PubMed=16959974; DOI=10.1126/science.1133427;
RA   Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D.,
RA   Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S.,
RA   Buckhaults P., Farrell C., Meeh P., Markowitz S.D., Willis J.,
RA   Dawson D., Willson J.K.V., Gazdar A.F., Hartigan J., Wu L., Liu C.,
RA   Parmigiani G., Park B.H., Bachman K.E., Papadopoulos N.,
RA   Vogelstein B., Kinzler K.W., Velculescu V.E.;
RT   "The consensus coding sequences of human breast and colorectal
RT   cancers.";
RL   Science 314:268-274(2006).
RN   [42]
RP   VARIANT [LARGE SCALE ANALYSIS] LEU-1141.
RX   PubMed=18987736; DOI=10.1038/nature07485;
RA   Ley T.J., Mardis E.R., Ding L., Fulton B., McLellan M.D., Chen K.,
RA   Dooling D., Dunford-Shore B.H., McGrath S., Hickenbotham M., Cook L.,
RA   Abbott R., Larson D.E., Koboldt D.C., Pohl C., Smith S., Hawkins A.,
RA   Abbott S., Locke D., Hillier L.W., Miner T., Fulton L., Magrini V.,
RA   Wylie T., Glasscock J., Conyers J., Sander N., Shi X., Osborne J.R.,
RA   Minx P., Gordon D., Chinwalla A., Zhao Y., Ries R.E., Payton J.E.,
RA   Westervelt P., Tomasson M.H., Watson M., Baty J., Ivanovich J.,
RA   Heath S., Shannon W.D., Nagarajan R., Walter M.J., Link D.C.,
RA   Graubert T.A., DiPersio J.F., Wilson R.K.;
RT   "DNA sequencing of a cytogenetically normal acute myeloid leukaemia
RT   genome.";
RL   Nature 456:66-72(2008).
CC   -!- FUNCTION: Multifunctional enzyme that has both magnesium and ATP-
CC       dependent DNA-helicase activity and 3'->5' exonuclease activity
CC       towards double-stranded DNA with a 5'-overhang. Has no nuclease
CC       activity towards single-stranded DNA or blunt-ended double-
CC       stranded DNA. Binds preferentially to DNA substrates containing
CC       alternate secondary structures, such as replication forks and
CC       Holliday junctions. May play an important role in the dissociation
CC       of joint DNA molecules that can arise as products of homologous
CC       recombination, at stalled replication forks or during DNA repair.
CC       Alleviates stalling of DNA polymerases at the site of DNA lesions.
CC       Important for genomic integrity. Plays a role in the formation of
CC       DNA replication focal centers; stably associates with foci
CC       elements generating binding sites for RP-A (By similarity). Plays
CC       a role in double-strand break repair after gamma-irradiation.
CC       {ECO:0000250, ECO:0000269|PubMed:11863428,
CC       ECO:0000269|PubMed:17563354, ECO:0000269|PubMed:18596042,
CC       ECO:0000269|PubMed:19283071, ECO:0000269|PubMed:19652551,
CC       ECO:0000269|PubMed:21639834}.
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=ATP + H2O = ADP + H(+) + phosphate; Xref=Rhea:RHEA:13065,
CC         ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616,
CC         ChEBI:CHEBI:43474, ChEBI:CHEBI:456216; EC=3.6.4.12;
CC         Evidence={ECO:0000269|PubMed:16622405};
CC   -!- COFACTOR:
CC       Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC         Evidence={ECO:0000269|PubMed:16622405};
CC       Name=Mn(2+); Xref=ChEBI:CHEBI:29035;
CC         Evidence={ECO:0000269|PubMed:16622405};
CC       Name=Zn(2+); Xref=ChEBI:CHEBI:29105;
CC         Evidence={ECO:0000269|PubMed:16622405};
CC       Note=Binds 2 magnesium ions per subunit. Has high activity with
CC       manganese and zinc ions (in vitro). {ECO:0000269|PubMed:16622405};
CC   -!- SUBUNIT: Monomer, and homooligomer. May exist as homodimer,
CC       homotrimer, homotetramer and/or homohexamer. Homotetramer, or
CC       homohexamer, when bound to DNA. Interacts via its N-terminal
CC       domain with WRNIP1 (By similarity). Interacts with EXO1, PCNA and
CC       SUPV3L1. Interacts with PML (isoform PML-4). {ECO:0000250,
CC       ECO:0000269|PubMed:11863428, ECO:0000269|PubMed:12704184,
CC       ECO:0000269|PubMed:17961633, ECO:0000269|PubMed:18596042,
CC       ECO:0000269|PubMed:20159463, ECO:0000269|PubMed:21639834}.
CC   -!- INTERACTION:
CC       P54132:BLM; NbExp=9; IntAct=EBI-368417, EBI-621372;
CC       P45973:CBX5; NbExp=3; IntAct=EBI-368417, EBI-78219;
CC       P39748:FEN1; NbExp=9; IntAct=EBI-368417, EBI-707816;
CC       P09874:PARP1; NbExp=8; IntAct=EBI-368417, EBI-355676;
CC       P43351:RAD52; NbExp=9; IntAct=EBI-368417, EBI-706448;
CC       P27694:RPA1; NbExp=9; IntAct=EBI-368417, EBI-621389;
CC       Q96EB6:SIRT1; NbExp=9; IntAct=EBI-368417, EBI-1802965;
CC       Q15554:TERF2; NbExp=8; IntAct=EBI-368417, EBI-706637;
CC       P04637:TP53; NbExp=5; IntAct=EBI-368417, EBI-366083;
CC       P12956:XRCC6; NbExp=6; IntAct=EBI-368417, EBI-353208;
CC   -!- SUBCELLULAR LOCATION: Nucleus, nucleolus
CC       {ECO:0000269|PubMed:9618508}. Nucleus
CC       {ECO:0000269|PubMed:17563354, ECO:0000269|PubMed:19652551}.
CC       Nucleus, nucleoplasm {ECO:0000269|PubMed:21639834}. Note=Gamma-
CC       irradiation leads to its translocation from nucleoli to
CC       nucleoplasm and PML regulates the irradiation-induced WRN
CC       relocation. {ECO:0000269|PubMed:21639834}.
CC   -!- PTM: Phosphorylated by PRKDC. {ECO:0000269|PubMed:11889123}.
CC   -!- DISEASE: Werner syndrome (WRN) [MIM:277700]: A rare autosomal
CC       recessive progeroid syndrome characterized by the premature onset
CC       of multiple age-related disorders, including atherosclerosis,
CC       cancer, non-insulin-dependent diabetes mellitus, ocular cataracts
CC       and osteoporosis. The major cause of death, at a median age of 47,
CC       is myocardial infarction. {ECO:0000269|PubMed:16673358}. Note=The
CC       disease is caused by mutations affecting the gene represented in
CC       this entry.
CC   -!- DISEASE: Colorectal cancer (CRC) [MIM:114500]: A complex disease
CC       characterized by malignant lesions arising from the inner wall of
CC       the large intestine (the colon) and the rectum. Genetic
CC       alterations are often associated with progression from
CC       premalignant lesion (adenoma) to invasive adenocarcinoma. Risk
CC       factors for cancer of the colon and rectum include colon polyps,
CC       long-standing ulcerative colitis, and genetic family history.
CC       {ECO:0000305|PubMed:24308539, ECO:0000305|PubMed:9989816}.
CC       Note=The disease may be caused by mutations affecting the gene
CC       represented in this entry.
CC   -!- SIMILARITY: Belongs to the helicase family. RecQ subfamily.
CC       {ECO:0000305}.
CC   -!- WEB RESOURCE: Name=WRN; Note=WRN mutation db (Warner disease);
CC       URL="http://www.pathology.washington.edu/werner/ws_wrn.html";
CC   -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology
CC       and Haematology;
CC       URL="http://atlasgeneticsoncology.org/Genes/WRNID284.html";
CC   -!- WEB RESOURCE: Name=NIEHS-SNPs;
CC       URL="http://egp.gs.washington.edu/data/wrn/";
DR   EMBL; L76937; AAC41981.1; -; Genomic_DNA.
DR   EMBL; AY818673; AAX21098.1; -; mRNA.
DR   EMBL; AF091214; AAC63361.1; -; mRNA.
DR   EMBL; AF181897; AAF06162.1; -; Genomic_DNA.
DR   EMBL; AF181896; AAF06162.1; JOINED; Genomic_DNA.
DR   EMBL; AY442327; AAR05448.1; -; Genomic_DNA.
DR   EMBL; AC084736; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   CCDS; CCDS6082.1; -.
DR   RefSeq; NP_000544.2; NM_000553.4.
DR   PDB; 2AXL; NMR; -; A=949-1092.
DR   PDB; 2DGZ; NMR; -; A=1140-1239.
DR   PDB; 2E1E; X-ray; 2.30 A; A=1142-1242.
DR   PDB; 2E1F; X-ray; 2.00 A; A=1142-1242.
DR   PDB; 2FBT; X-ray; 2.05 A; A=38-236.
DR   PDB; 2FBV; X-ray; 2.40 A; A=38-236.
DR   PDB; 2FBX; X-ray; 2.20 A; A=38-236.
DR   PDB; 2FBY; X-ray; 2.00 A; A=38-236.
DR   PDB; 2FC0; X-ray; 2.00 A; A=38-236.
DR   PDB; 3AAF; X-ray; 1.90 A; A/B=949-1079.
DR   PDBsum; 2AXL; -.
DR   PDBsum; 2DGZ; -.
DR   PDBsum; 2E1E; -.
DR   PDBsum; 2E1F; -.
DR   PDBsum; 2FBT; -.
DR   PDBsum; 2FBV; -.
DR   PDBsum; 2FBX; -.
DR   PDBsum; 2FBY; -.
DR   PDBsum; 2FC0; -.
DR   PDBsum; 3AAF; -.
DR   SMR; Q14191; -.
DR   BioGrid; 113323; 60.
DR   CORUM; Q14191; -.
DR   DIP; DIP-31380N; -.
DR   ELM; Q14191; -.
DR   IntAct; Q14191; 33.
DR   MINT; Q14191; -.
DR   STRING; 9606.ENSP00000298139; -.
DR   BindingDB; Q14191; -.
DR   ChEMBL; CHEMBL2146312; -.
DR   iPTMnet; Q14191; -.
DR   PhosphoSitePlus; Q14191; -.
DR   BioMuta; WRN; -.
DR   DMDM; 322510082; -.
DR   EPD; Q14191; -.
DR   jPOST; Q14191; -.
DR   MassIVE; Q14191; -.
DR   MaxQB; Q14191; -.
DR   PaxDb; Q14191; -.
DR   PeptideAtlas; Q14191; -.
DR   PRIDE; Q14191; -.
DR   ProteomicsDB; 59913; -.
DR   Ensembl; ENST00000298139; ENSP00000298139; ENSG00000165392.
DR   GeneID; 7486; -.
DR   KEGG; hsa:7486; -.
DR   UCSC; uc003xio.5; human.
DR   CTD; 7486; -.
DR   DisGeNET; 7486; -.
DR   GeneCards; WRN; -.
DR   GeneReviews; WRN; -.
DR   HGNC; HGNC:12791; WRN.
DR   HPA; HPA028661; -.
DR   MalaCards; WRN; -.
DR   MIM; 114500; phenotype.
DR   MIM; 277700; phenotype.
DR   MIM; 604611; gene.
DR   neXtProt; NX_Q14191; -.
DR   OpenTargets; ENSG00000165392; -.
DR   Orphanet; 902; Werner syndrome.
DR   PharmGKB; PA367; -.
DR   eggNOG; KOG0351; Eukaryota.
DR   eggNOG; KOG4373; Eukaryota.
DR   eggNOG; COG0514; LUCA.
DR   GeneTree; ENSGT00940000159168; -.
DR   HOGENOM; HOG000146447; -.
DR   InParanoid; Q14191; -.
DR   KO; K10900; -.
DR   OMA; RCFPNSE; -.
DR   OrthoDB; 445763at2759; -.
DR   PhylomeDB; Q14191; -.
DR   TreeFam; TF312852; -.
DR   BRENDA; 3.6.4.12; 2681.
DR   Reactome; R-HSA-3108214; SUMOylation of DNA damage response and repair proteins.
DR   Reactome; R-HSA-5685938; HDR through Single Strand Annealing (SSA).
DR   Reactome; R-HSA-5685942; HDR through Homologous Recombination (HRR).
DR   Reactome; R-HSA-5693554; Resolution of D-loop Structures through Synthesis-Dependent Strand Annealing (SDSA).
DR   Reactome; R-HSA-5693568; Resolution of D-loop Structures through Holliday Junction Intermediates.
DR   Reactome; R-HSA-5693579; Homologous DNA Pairing and Strand Exchange.
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-6804756; Regulation of TP53 Activity through Phosphorylation.
DR   Reactome; R-HSA-69473; G2/M DNA damage checkpoint.
DR   SIGNOR; Q14191; -.
DR   ChiTaRS; WRN; human.
DR   EvolutionaryTrace; Q14191; -.
DR   GeneWiki; Werner_syndrome_ATP-dependent_helicase; -.
DR   GenomeRNAi; 7486; -.
DR   Pharos; Q14191; -.
DR   PRO; PR:Q14191; -.
DR   Proteomes; UP000005640; Chromosome 8.
DR   Bgee; ENSG00000165392; Expressed in 199 organ(s), highest expression level in sperm.
DR   Genevisible; Q14191; HS.
DR   GO; GO:0005813; C:centrosome; IDA:UniProtKB.
DR   GO; GO:0005694; C:chromosome; IBA:GO_Central.
DR   GO; GO:0000781; C:chromosome, telomeric region; IDA:BHF-UCL.
DR   GO; GO:0005737; C:cytoplasm; IBA:GO_Central.
DR   GO; GO:0043005; C:neuron projection; IEA:Ensembl.
DR   GO; GO:0016607; C:nuclear speck; IDA:HPA.
DR   GO; GO:0005730; C:nucleolus; IDA:UniProtKB.
DR   GO; GO:0005654; C:nucleoplasm; IDA:UniProtKB.
DR   GO; GO:0005634; C:nucleus; IBA:GO_Central.
DR   GO; GO:0005657; C:replication fork; ISS:BHF-UCL.
DR   GO; GO:0043138; F:3'-5' DNA helicase activity; IDA:UniProtKB.
DR   GO; GO:0008408; F:3'-5' exonuclease activity; IDA:UniProtKB.
DR   GO; GO:0070337; F:3'-flap-structured DNA binding; IDA:BHF-UCL.
DR   GO; GO:1905773; F:8-hydroxy-2'-deoxyguanosine DNA binding; IDA:BHF-UCL.
DR   GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR   GO; GO:0016887; F:ATPase activity; IDA:UniProtKB.
DR   GO; GO:0000405; F:bubble DNA binding; IDA:UniProtKB.
DR   GO; GO:0003682; F:chromatin binding; IEA:Ensembl.
DR   GO; GO:0003677; F:DNA binding; IDA:UniProtKB.
DR   GO; GO:0003678; F:DNA helicase activity; IDA:UniProtKB.
DR   GO; GO:0004527; F:exonuclease activity; IDA:MGI.
DR   GO; GO:0061749; F:forked DNA-dependent helicase activity; IDA:BHF-UCL.
DR   GO; GO:0000400; F:four-way junction DNA binding; IDA:BHF-UCL.
DR   GO; GO:0009378; F:four-way junction helicase activity; IDA:UniProtKB.
DR   GO; GO:0051880; F:G-quadruplex DNA binding; IDA:UniProtKB.
DR   GO; GO:0004386; F:helicase activity; IDA:UniProtKB.
DR   GO; GO:0000287; F:magnesium ion binding; IDA:UniProtKB.
DR   GO; GO:0030145; F:manganese ion binding; IDA:UniProtKB.
DR   GO; GO:0032405; F:MutLalpha complex binding; IDA:UniProtKB.
DR   GO; GO:0042803; F:protein homodimerization activity; IDA:UniProtKB.
DR   GO; GO:0044877; F:protein-containing complex binding; IDA:UniProtKB.
DR   GO; GO:0061821; F:telomeric D-loop binding; IDA:BHF-UCL.
DR   GO; GO:0061849; F:telomeric G-quadruplex DNA binding; IC:BHF-UCL.
DR   GO; GO:0000403; F:Y-form DNA binding; IDA:UniProtKB.
DR   GO; GO:0007568; P:aging; NAS:UniProtKB.
DR   GO; GO:0006284; P:base-excision repair; IDA:UniProtKB.
DR   GO; GO:0007420; P:brain development; IEA:Ensembl.
DR   GO; GO:0007569; P:cell aging; IMP: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:UniProtKB.
DR   GO; GO:0009267; P:cellular response to starvation; IDA:MGI.
DR   GO; GO:0032508; P:DNA duplex unwinding; IDA:BHF-UCL.
DR   GO; GO:0006259; P:DNA metabolic process; IDA:UniProtKB.
DR   GO; GO:0006310; P:DNA recombination; IBA:GO_Central.
DR   GO; GO:0006281; P:DNA repair; IBA:GO_Central.
DR   GO; GO:0006260; P:DNA replication; IMP:UniProtKB.
DR   GO; GO:0000731; P:DNA synthesis involved in DNA repair; IDA:UniProtKB.
DR   GO; GO:0006268; P:DNA unwinding involved in DNA replication; IBA:GO_Central.
DR   GO; GO:0006302; P:double-strand break repair; IMP:UniProtKB.
DR   GO; GO:0000724; P:double-strand break repair via homologous recombination; IBA:GO_Central.
DR   GO; GO:0044806; P:G-quadruplex DNA unwinding; IDA:BHF-UCL.
DR   GO; GO:0010259; P:multicellular organism aging; IMP:UniProtKB.
DR   GO; GO:0051345; P:positive regulation of hydrolase activity; IDA:UniProtKB.
DR   GO; GO:0098530; P:positive regulation of strand invasion; IDA:BHF-UCL.
DR   GO; GO:1902570; P:protein localization to nucleolus; IDA:MGI.
DR   GO; GO:0042981; P:regulation of apoptotic process; IGI:MGI.
DR   GO; GO:0040009; P:regulation of growth rate; IEA:Ensembl.
DR   GO; GO:1901796; P:regulation of signal transduction by p53 class mediator; TAS:Reactome.
DR   GO; GO:0031297; P:replication fork processing; IDA:UniProtKB.
DR   GO; GO:0001302; P:replicative cell aging; IEA:Ensembl.
DR   GO; GO:0006979; P:response to oxidative stress; IDA:UniProtKB.
DR   GO; GO:0010225; P:response to UV-C; IDA:UniProtKB.
DR   GO; GO:0090656; P:t-circle formation; TAS:BHF-UCL.
DR   GO; GO:0000723; P:telomere maintenance; IMP:UniProtKB.
DR   GO; GO:0061820; P:telomeric D-loop disassembly; IDA:BHF-UCL.
DR   DisProt; DP00443; -.
DR   Gene3D; 1.10.10.10; -; 1.
DR   Gene3D; 3.30.420.10; -; 1.
DR   InterPro; IPR002562; 3'-5'_exonuclease_dom.
DR   InterPro; IPR011545; DEAD/DEAH_box_helicase_dom.
DR   InterPro; IPR004589; DNA_helicase_ATP-dep_RecQ.
DR   InterPro; IPR014001; Helicase_ATP-bd.
DR   InterPro; IPR001650; Helicase_C.
DR   InterPro; IPR029491; Helicase_HTH.
DR   InterPro; IPR010997; HRDC-like_sf.
DR   InterPro; IPR002121; HRDC_dom.
DR   InterPro; IPR027417; P-loop_NTPase.
DR   InterPro; IPR032284; RecQ_Zn-bd.
DR   InterPro; IPR012337; RNaseH-like_sf.
DR   InterPro; IPR036397; RNaseH_sf.
DR   InterPro; IPR018982; RQC_domain.
DR   InterPro; IPR036388; WH-like_DNA-bd_sf.
DR   InterPro; IPR036390; WH_DNA-bd_sf.
DR   Pfam; PF00270; DEAD; 1.
DR   Pfam; PF01612; DNA_pol_A_exo1; 1.
DR   Pfam; PF00271; Helicase_C; 1.
DR   Pfam; PF00570; HRDC; 1.
DR   Pfam; PF14493; HTH_40; 1.
DR   Pfam; PF16124; RecQ_Zn_bind; 1.
DR   Pfam; PF09382; RQC; 1.
DR   SMART; SM00474; 35EXOc; 1.
DR   SMART; SM00487; DEXDc; 1.
DR   SMART; SM00490; HELICc; 1.
DR   SMART; SM00341; HRDC; 1.
DR   SMART; SM00956; RQC; 1.
DR   SUPFAM; SSF46785; SSF46785; 1.
DR   SUPFAM; SSF47819; SSF47819; 1.
DR   SUPFAM; SSF52540; SSF52540; 1.
DR   SUPFAM; SSF53098; SSF53098; 1.
DR   TIGRFAMs; TIGR00614; recQ_fam; 1.
DR   PROSITE; PS51192; HELICASE_ATP_BIND_1; 1.
DR   PROSITE; PS51194; HELICASE_CTER; 1.
DR   PROSITE; PS50967; HRDC; 1.
PE   1: Evidence at protein level;
KW   3D-structure; Acetylation; ATP-binding; Complete proteome;
KW   Direct protein sequencing; Disease mutation; DNA damage; DNA repair;
KW   DNA-binding; Exonuclease; Helicase; Hydrolase; Isopeptide bond;
KW   Magnesium; Metal-binding; Multifunctional enzyme; Nuclease;
KW   Nucleotide-binding; Nucleus; Phosphoprotein; Polymorphism;
KW   Reference proteome; Repeat; Ubl conjugation; Zinc.
FT   INIT_MET      1      1       Removed. {ECO:0000244|PubMed:22814378}.
FT   CHAIN         2   1432       Werner syndrome ATP-dependent helicase.
FT                                /FTId=PRO_0000205045.
FT   DOMAIN       60    228       3'-5' exonuclease.
FT   REPEAT      424    450       1. {ECO:0000269|PubMed:10049920}.
FT   REPEAT      451    477       2. {ECO:0000269|PubMed:10049920}.
FT   DOMAIN      558    724       Helicase ATP-binding.
FT                                {ECO:0000255|PROSITE-ProRule:PRU00541}.
FT   DOMAIN      749    899       Helicase C-terminal.
FT                                {ECO:0000255|PROSITE-ProRule:PRU00542}.
FT   DOMAIN     1150   1229       HRDC. {ECO:0000255|PROSITE-
FT                                ProRule:PRU00328}.
FT   NP_BIND     571    578       ATP. {ECO:0000255|PROSITE-
FT                                ProRule:PRU00541}.
FT   REGION        2    277       Interaction with WRNIP1. {ECO:0000250}.
FT   REGION      424    477       2 X 27 AA tandem repeats of H-L-S-P-N-D-
FT                                N-E-N-D-T-S-Y-V-I-E-S-D-E-D-L-E-M-E-M-L-
FT                                K.
FT   REGION      987    993       Interaction with DNA.
FT                                {ECO:0000269|PubMed:20159463}.
FT   MOTIF       668    671       DEAH box.
FT   COMPBIAS    507    510       Poly-Glu.
FT   METAL        82     82       Magnesium 1; catalytic.
FT                                {ECO:0000244|PDB:2FBV,
FT                                ECO:0000244|PDB:2FBX,
FT                                ECO:0000244|PDB:2FC0,
FT                                ECO:0000269|PubMed:16622405}.
FT   METAL        82     82       Magnesium 2; catalytic.
FT                                {ECO:0000244|PDB:2FBV,
FT                                ECO:0000244|PDB:2FBX,
FT                                ECO:0000244|PDB:2FC0,
FT                                ECO:0000269|PubMed:16622405}.
FT   METAL        84     84       Magnesium 1; catalytic.
FT                                {ECO:0000244|PDB:2FBV,
FT                                ECO:0000244|PDB:2FBX,
FT                                ECO:0000244|PDB:2FC0,
FT                                ECO:0000269|PubMed:16622405}.
FT   METAL       216    216       Magnesium 1; catalytic.
FT                                {ECO:0000244|PDB:2FBV,
FT                                ECO:0000244|PDB:2FBX,
FT                                ECO:0000244|PDB:2FC0,
FT                                ECO:0000269|PubMed:16622405}.
FT   SITE        145    145       Interaction with DNA. {ECO:0000305}.
FT   SITE       1037   1037       Interaction with DNA.
FT   MOD_RES       2      2       N-acetylserine.
FT                                {ECO:0000244|PubMed:22814378}.
FT   MOD_RES     426    426       Phosphoserine.
FT                                {ECO:0000244|PubMed:19690332}.
FT   MOD_RES     440    440       Phosphoserine.
FT                                {ECO:0000244|PubMed:18669648,
FT                                ECO:0000244|PubMed:19690332}.
FT   MOD_RES     453    453       Phosphoserine.
FT                                {ECO:0000244|PubMed:19690332}.
FT   MOD_RES     467    467       Phosphoserine.
FT                                {ECO:0000244|PubMed:18669648,
FT                                ECO:0000244|PubMed:19690332}.
FT   MOD_RES     478    478       Phosphoserine.
FT                                {ECO:0000244|PubMed:23186163}.
FT   MOD_RES    1133   1133       Phosphoserine.
FT                                {ECO:0000244|PubMed:21406692,
FT                                ECO:0000244|PubMed:23186163}.
FT   MOD_RES    1400   1400       Phosphoserine.
FT                                {ECO:0000244|PubMed:23186163}.
FT   CROSSLNK    154    154       Glycyl lysine isopeptide (Lys-Gly)
FT                                (interchain with G-Cter in SUMO2).
FT                                {ECO:0000244|PubMed:28112733}.
FT   CROSSLNK    241    241       Glycyl lysine isopeptide (Lys-Gly)
FT                                (interchain with G-Cter in SUMO2).
FT                                {ECO:0000244|PubMed:28112733}.
FT   CROSSLNK    252    252       Glycyl lysine isopeptide (Lys-Gly)
FT                                (interchain with G-Cter in SUMO2).
FT                                {ECO:0000244|PubMed:28112733}.
FT   VARIANT      32     32       K -> R (in dbSNP:rs34477820).
FT                                {ECO:0000269|PubMed:11161804}.
FT                                /FTId=VAR_017453.
FT   VARIANT      92     92       G -> V (in a colorectal cancer sample;
FT                                somatic mutation).
FT                                {ECO:0000269|PubMed:16959974}.
FT                                /FTId=VAR_036318.
FT   VARIANT     114    114       V -> I (polymorphism; no effect on
FT                                exonuclease activity; dbSNP:rs2230009).
FT                                {ECO:0000269|PubMed:11161804,
FT                                ECO:0000269|PubMed:16622405,
FT                                ECO:0000269|Ref.4}.
FT                                /FTId=VAR_017454.
FT   VARIANT     125    125       K -> N (in WRN; dbSNP:rs387906337).
FT                                {ECO:0000269|PubMed:16673358}.
FT                                /FTId=VAR_026588.
FT   VARIANT     135    135       K -> E (in WRN; dbSNP:rs267607008).
FT                                {ECO:0000269|PubMed:16673358}.
FT                                /FTId=VAR_026589.
FT   VARIANT     172    172       T -> P (polymorphism; no effect on
FT                                exonuclease activity; dbSNP:rs367991517).
FT                                {ECO:0000269|PubMed:11161804,
FT                                ECO:0000269|PubMed:16622405}.
FT                                /FTId=VAR_017455.
FT   VARIANT     240    240       N -> K (in dbSNP:rs148229804).
FT                                {ECO:0000269|PubMed:11161804}.
FT                                /FTId=VAR_017456.
FT   VARIANT     324    324       T -> A (in dbSNP:rs1800390).
FT                                {ECO:0000269|PubMed:10069711}.
FT                                /FTId=VAR_006904.
FT   VARIANT     329    329       Q -> R (in dbSNP:rs4987237).
FT                                /FTId=VAR_020450.
FT   VARIANT     343    343       E -> K (in dbSNP:rs11574222).
FT                                {ECO:0000269|Ref.4}.
FT                                /FTId=VAR_018941.
FT   VARIANT     383    383       L -> F (in dbSNP:rs4987238).
FT                                /FTId=VAR_020451.
FT   VARIANT     383    383       L -> W. {ECO:0000269|PubMed:11161804}.
FT                                /FTId=VAR_017457.
FT   VARIANT     387    387       M -> I (in dbSNP:rs1800391).
FT                                {ECO:0000269|PubMed:10206685,
FT                                ECO:0000269|PubMed:11161804,
FT                                ECO:0000269|PubMed:9450180,
FT                                ECO:0000269|Ref.4}.
FT                                /FTId=VAR_006905.
FT   VARIANT     533    533       N -> S (in dbSNP:rs11574240).
FT                                {ECO:0000269|Ref.4}.
FT                                /FTId=VAR_018942.
FT   VARIANT     612    612       S -> C (in dbSNP:rs11574250).
FT                                {ECO:0000269|Ref.4}.
FT                                /FTId=VAR_018943.
FT   VARIANT     708    708       S -> F (in dbSNP:rs11574289).
FT                                {ECO:0000269|Ref.4}.
FT                                /FTId=VAR_018944.
FT   VARIANT     711    711       R -> W (in dbSNP:rs34560788).
FT                                /FTId=VAR_057124.
FT   VARIANT     724    724       Q -> L. {ECO:0000269|PubMed:11161804}.
FT                                /FTId=VAR_017458.
FT   VARIANT     834    834       R -> C (in dbSNP:rs3087425).
FT                                {ECO:0000269|Ref.4}.
FT                                /FTId=VAR_014913.
FT   VARIANT     912    912       I -> S (in dbSNP:rs11574323).
FT                                {ECO:0000269|Ref.4}.
FT                                /FTId=VAR_018945.
FT   VARIANT    1074   1074       L -> F (in dbSNP:rs1801195).
FT                                {ECO:0000269|PubMed:11161804,
FT                                ECO:0000269|PubMed:16723399,
FT                                ECO:0000269|PubMed:8602509,
FT                                ECO:0000269|PubMed:9450180,
FT                                ECO:0000269|Ref.3}.
FT                                /FTId=VAR_007903.
FT   VARIANT    1079   1079       S -> L (in dbSNP:rs3087414).
FT                                {ECO:0000269|Ref.4}.
FT                                /FTId=VAR_014914.
FT   VARIANT    1133   1133       S -> A (in dbSNP:rs11574358).
FT                                {ECO:0000269|Ref.4}.
FT                                /FTId=VAR_018946.
FT   VARIANT    1141   1141       S -> L (in dbSNP:rs139323683).
FT                                {ECO:0000269|PubMed:18987736}.
FT                                /FTId=VAR_054162.
FT   VARIANT    1269   1269       K -> E (in dbSNP:rs746648510).
FT                                {ECO:0000269|PubMed:11161804}.
FT                                /FTId=VAR_017459.
FT   VARIANT    1339   1339       V -> I (in dbSNP:rs11574395).
FT                                {ECO:0000269|Ref.4}.
FT                                /FTId=VAR_018947.
FT   VARIANT    1367   1367       C -> R (polymorphism associated with a
FT                                higher risk of myocardial infarction;
FT                                dbSNP:rs1346044).
FT                                {ECO:0000269|PubMed:10069711,
FT                                ECO:0000269|PubMed:11161804,
FT                                ECO:0000269|PubMed:9021029,
FT                                ECO:0000269|Ref.4}.
FT                                /FTId=VAR_006906.
FT   MUTAGEN      84     84       E->A: Abolishes exonuclease activity.
FT                                {ECO:0000269|PubMed:11863428,
FT                                ECO:0000269|PubMed:16622405}.
FT   MUTAGEN      88     88       L->A: No effect on exonuclease activity.
FT   MUTAGEN     145    145       W->A: Reduces exonuclease activity.
FT                                {ECO:0000269|PubMed:16622405}.
FT   MUTAGEN     212    212       Y->F: Strongly reduces exonuclease
FT                                activity. {ECO:0000269|PubMed:16622405}.
FT   MUTAGEN     987    987       R->A: Reduces affinity for DNA about 8-
FT                                fold. Loss of DNA binding; when
FT                                associated with A-993.
FT                                {ECO:0000269|PubMed:20159463}.
FT   MUTAGEN     989    989       S->A: Reduces affinity for DNA about 4-
FT                                fold. {ECO:0000269|PubMed:20159463}.
FT   MUTAGEN     993    993       R->A: Reduces affinity for DNA about 20-
FT                                fold. Loss of DNA binding; when
FT                                associated with A-987.
FT                                {ECO:0000269|PubMed:20159463}.
FT   MUTAGEN     993    993       R->E: Loss of DNA binding.
FT                                {ECO:0000269|PubMed:20159463}.
FT   MUTAGEN    1037   1037       F->A: Reduces affinity for DNA about 8-
FT                                fold. {ECO:0000269|PubMed:20159463}.
FT   MUTAGEN    1038   1038       M->A: Reduces affinity for DNA about 4-
FT                                fold. {ECO:0000269|PubMed:20159463}.
FT   HELIX        39     41       {ECO:0000244|PDB:2FBY}.
FT   STRAND       51     56       {ECO:0000244|PDB:2FBY}.
FT   HELIX        59     72       {ECO:0000244|PDB:2FBY}.
FT   STRAND       78     84       {ECO:0000244|PDB:2FBY}.
FT   STRAND       99    105       {ECO:0000244|PDB:2FBY}.
FT   STRAND      108    112       {ECO:0000244|PDB:2FBY}.
FT   HELIX       114    116       {ECO:0000244|PDB:2FBY}.
FT   STRAND      117    119       {ECO:0000244|PDB:2FBY}.
FT   HELIX       122    128       {ECO:0000244|PDB:2FBY}.
FT   STRAND      133    139       {ECO:0000244|PDB:2FBY}.
FT   HELIX       140    151       {ECO:0000244|PDB:2FBY}.
FT   STRAND      157    160       {ECO:0000244|PDB:2FBY}.
FT   HELIX       161    169       {ECO:0000244|PDB:2FBY}.
FT   HELIX       177    185       {ECO:0000244|PDB:2FBY}.
FT   HELIX       193    196       {ECO:0000244|PDB:2FBY}.
FT   STRAND      202    204       {ECO:0000244|PDB:2FBY}.
FT   HELIX       207    228       {ECO:0000244|PDB:2FBY}.
FT   STRAND      955    958       {ECO:0000244|PDB:2AXL}.
FT   HELIX       960    972       {ECO:0000244|PDB:3AAF}.
FT   TURN        973    975       {ECO:0000244|PDB:3AAF}.
FT   HELIX       980    986       {ECO:0000244|PDB:3AAF}.
FT   HELIX       996   1000       {ECO:0000244|PDB:3AAF}.
FT   TURN       1002   1009       {ECO:0000244|PDB:3AAF}.
FT   HELIX      1012   1024       {ECO:0000244|PDB:3AAF}.
FT   STRAND     1027   1032       {ECO:0000244|PDB:3AAF}.
FT   TURN       1036   1038       {ECO:0000244|PDB:2AXL}.
FT   STRAND     1039   1043       {ECO:0000244|PDB:3AAF}.
FT   HELIX      1045   1054       {ECO:0000244|PDB:3AAF}.
FT   STRAND     1062   1064       {ECO:0000244|PDB:2AXL}.
FT   HELIX      1147   1171       {ECO:0000244|PDB:2E1F}.
FT   HELIX      1175   1178       {ECO:0000244|PDB:2E1F}.
FT   HELIX      1181   1190       {ECO:0000244|PDB:2E1F}.
FT   HELIX      1195   1198       {ECO:0000244|PDB:2E1F}.
FT   STRAND     1201   1203       {ECO:0000244|PDB:2DGZ}.
FT   HELIX      1206   1211       {ECO:0000244|PDB:2E1F}.
FT   HELIX      1213   1225       {ECO:0000244|PDB:2E1F}.
SQ   SEQUENCE   1432 AA;  162461 MW;  63F10D19E90AA461 CRC64;
     MSEKKLETTA QQRKCPEWMN VQNKRCAVEE RKACVRKSVF EDDLPFLEFT GSIVYSYDAS
     DCSFLSEDIS MSLSDGDVVG FDMEWPPLYN RGKLGKVALI QLCVSESKCY LFHVSSMSVF
     PQGLKMLLEN KAVKKAGVGI EGDQWKLLRD FDIKLKNFVE LTDVANKKLK CTETWSLNSL
     VKHLLGKQLL KDKSIRCSNW SKFPLTEDQK LYAATDAYAG FIIYRNLEIL DDTVQRFAIN
     KEEEILLSDM NKQLTSISEE VMDLAKHLPH AFSKLENPRR VSILLKDISE NLYSLRRMII
     GSTNIETELR PSNNLNLLSF EDSTTGGVQQ KQIREHEVLI HVEDETWDPT LDHLAKHDGE
     DVLGNKVERK EDGFEDGVED NKLKENMERA CLMSLDITEH ELQILEQQSQ EEYLSDIAYK
     STEHLSPNDN ENDTSYVIES DEDLEMEMLK HLSPNDNEND TSYVIESDED LEMEMLKSLE
     NLNSGTVEPT HSKCLKMERN LGLPTKEEEE DDENEANEGE EDDDKDFLWP APNEEQVTCL
     KMYFGHSSFK PVQWKVIHSV LEERRDNVAV MATGYGKSLC FQYPPVYVGK IGLVISPLIS
     LMEDQVLQLK MSNIPACFLG SAQSENVLTD IKLGKYRIVY VTPEYCSGNM GLLQQLEADI
     GITLIAVDEA HCISEWGHDF RDSFRKLGSL KTALPMVPIV ALTATASSSI REDIVRCLNL
     RNPQITCTGF DRPNLYLEVR RKTGNILQDL QPFLVKTSSH WEFEGPTIIY CPSRKMTQQV
     TGELRKLNLS CGTYHAGMSF STRKDIHHRF VRDEIQCVIA TIAFGMGINK ADIRQVIHYG
     APKDMESYYQ EIGRAGRDGL QSSCHVLWAP ADINLNRHLL TEIRNEKFRL YKLKMMAKME
     KYLHSSRCRR QIILSHFEDK QVQKASLGIM GTEKCCDNCR SRLDHCYSMD DSEDTSWDFG
     PQAFKLLSAV DILGEKFGIG LPILFLRGSN SQRLADQYRR HSLFGTGKDQ TESWWKAFSR
     QLITEGFLVE VSRYNKFMKI CALTKKGRNW LHKANTESQS LILQANEELC PKKLLLPSSK
     TVSSGTKEHC YNQVPVELST EKKSNLEKLY SYKPCDKISS GSNISKKSIM VQSPEKAYSS
     SQPVISAQEQ ETQIVLYGKL VEARQKHANK MDVPPAILAT NKILVDMAKM RPTTVENVKR
     IDGVSEGKAA MLAPLLEVIK HFCQTNSVQT DLFSSTKPQE EQKTSLVAKN KICTLSQSMA
     ITYSLFQEKK MPLKSIAESR ILPLMTIGMH LSQAVKAGCP LDLERAGLTP EVQKIIADVI
     RNPPVNSDMS KISLIRMLVP ENIDTYLIHM AIEILKHGPD SGLQPSCDVN KRRCFPGSEE
     ICSSSKRSKE EVGINTETSS AERKRRLPVW FAKGSDTSKK LMDKTKRGGL FS
//
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