WRN_HUMAN
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 03-AUG-2022, entry version 234.
DE RecName: Full=Bifunctional 3'-5' exonuclease/ATP-dependent helicase WRN {ECO:0000305};
DE AltName: Full=DNA helicase, RecQ-like type 3;
DE AltName: Full=RecQ protein-like 2;
DE AltName: Full=Werner syndrome protein {ECO:0000303|PubMed:9618508};
DE Includes:
DE RecName: Full=3'-5' exonuclease;
DE EC=3.1.-.- {ECO:0000269|PubMed:11863428};
DE Includes:
DE RecName: Full=ATP-dependent helicase;
DE EC=3.6.4.12 {ECO:0000269|PubMed:16622405};
GN Name=WRN; Synonyms=RECQ3, RECQL2;
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 [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 in
RT 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; ILE-387;
RP SER-533; CYS-612; PHE-708; CYS-834; SER-912; LEU-1079; ALA-1133; ILE-1339
RP 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., Garber M.,
RA Kodira C.D., Schueler M.G., Shimizu A., Whittaker C.A., Chang J.L.,
RA Cuomo C.A., Dewar K., FitzGerald M.G., Yang X., Allen N.R., Anderson S.,
RA Asakawa T., Blechschmidt K., Bloom T., Borowsky M.L., Butler J., Cook A.,
RA Corum B., DeArellano K., DeCaprio D., Dooley K.T., Dorris L. III,
RA Engels R., Gloeckner G., Hafez N., Hagopian D.S., Hall J.L., Ishikawa S.K.,
RA Jaffe D.B., 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., O'Leary S.B.,
RA O'Neill K., Parker S.C.J., Polley A., Raymond C.K., Reichwald K.,
RA Rodriguez J., Sasaki T., Schilhabel M., Siddiqui R., Smith C.L.,
RA Sneddon T.P., Talamas J.A., Tenzin P., Topham K., Venkataraman V., Wen G.,
RA Yamazaki S., Young S.K., Zeng Q., Zimmer A.R., Rosenthal A., Birren B.W.,
RA Platzer M., Shimizu N., 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 cells.";
RL Proc. Natl. Acad. Sci. U.S.A. 95:6887-6892(1998).
RN [7]
RP REPEATS.
RX PubMed=10049920; DOI=10.1093/genetics/151.3.1027;
RA Kusano K., Berres M.E., Engels W.R.;
RT "Evolution of the RECQ family of helicases: a Drosophila homolog, Dmblm, is
RT 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., Armstrong S.,
RA Knowles M.A., Takle L.A., Kuo M., Khan N., Phillips S.M., Neoptolemos J.P.,
RA Morton D.G.;
RT "Two novel regions of interstitial deletion on chromosome 8p in colorectal
RT cancer.";
RL Oncogene 18:657-665(1999).
RN [9]
RP FUNCTION, MUTAGENESIS OF GLU-84, FUNCTION AS AN EXONUCLEASE, DNA-BINDING,
RP 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., Erie D.A.,
RA Redinbo M.R.;
RT "A minimal exonuclease domain of WRN forms a hexamer on DNA and possesses
RT both 3'- 5' exonuclease and 5'-protruding strand 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 and in
RT vitro, and its catalytic activities are regulated by 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-terminal
RT 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., Bartnik E.,
RA Klysik J., Bohr V.A., Stepien P.P.;
RT "Interaction of human SUV3 RNA/DNA helicase with BLM helicase; loss of the
RT 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, Hurov K.E.,
RA Luo J., Bakalarski C.E., Zhao Z., Solimini N., Lerenthal Y., Shiloh Y.,
RA 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 junction
RT 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., 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 [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 through
RT 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 AND
RP SER-467, AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE 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., 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 [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 helicase and
RT regulates double-strand break repair in gamma-irradiation-induced DNA
RT damage responses.";
RL Biochemistry (Mosc.) 76:550-554(2011).
RN [23]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1133, AND IDENTIFICATION BY
RP 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 [24]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT SER-2, CLEAVAGE OF INITIATOR
RP METHIONINE [LARGE SCALE ANALYSIS], AND IDENTIFICATION BY MASS SPECTROMETRY
RP [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., Timmerman E.,
RA Prieto J., Arnesen T., Sherman F., Gevaert K., Aldabe R.;
RT "N-terminal acetylome analyses and functional insights of the N-terminal
RT 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 delineating
RT 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 SER-1400,
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 [27]
RP FUNCTION, SUBCELLULAR LOCATION, INTERACTION WITH XRCC5 AND XRCC6, DOMAIN,
RP XLM MOTIF, KBM MOTIFS, AND MUTAGENESIS OF TRP-18 AND GLU-84.
RX PubMed=27063109; DOI=10.1038/ncomms11242;
RA Grundy G.J., Rulten S.L., Arribas-Bosacoma R., Davidson K., Kozik Z.,
RA Oliver A.W., Pearl L.H., Caldecott K.W.;
RT "The Ku-binding motif is a conserved module for recruitment and stimulation
RT of non-homologous end-joining proteins.";
RL Nat. Commun. 7:11242-11242(2016).
RN [28]
RP SUMOYLATION [LARGE SCALE ANALYSIS] AT LYS-154; LYS-241 AND LYS-252, AND
RP 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-modification
RT with phosphorylation.";
RL Nat. Struct. Mol. Biol. 24:325-336(2017).
RN [29]
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 motif of
RT human Werner syndrome protein.";
RL Proc. Natl. Acad. Sci. U.S.A. 102:18379-18384(2005).
RN [30]
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., Han S.,
RA Cooper P.K., Chen D.J., Tainer J.A.;
RT "WRN exonuclease structure and molecular mechanism imply an editing role in
RT DNA end processing.";
RL Nat. Struct. Mol. Biol. 13:414-422(2006).
RN [31]
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 [32]
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 Werner
RT syndrome ATP-dependent helicase.";
RL Submitted (SEP-2006) to the PDB data bank.
RN [33]
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 protein,
RT WRN.";
RL J. Biol. Chem. 282:2717-2728(2007).
RN [34]
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 winged-
RT helix domain of RecQ helicase WRN.";
RL Structure 18:177-187(2010).
RN [35]
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., Ikegami H.,
RA 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 [36]
RP ERRATUM OF PUBMED:9021029.
RA Ye L., Miki T., Nakura J., Oshima J., Kamino K., Rakugi H., Ikegami H.,
RA Higaki J., Edland S.D., Martin G.M., Ogihara T.;
RL Am. J. Med. Genet. 70:103-103(1997).
RN [37]
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 [38]
RP SUBCELLULAR LOCATION, AND INTERACTION WITH RECQL5.
RX PubMed=23180761; DOI=10.1093/nar/gks1134;
RA Popuri V., Huang J., Ramamoorthy M., Tadokoro T., Croteau D.L., Bohr V.A.;
RT "RECQL5 plays co-operative and complementary roles with WRN syndrome
RT helicase.";
RL Nucleic Acids Res. 41:881-899(2013).
RN [39]
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 of
RT the WRN gene detected in a French Werner family with a severe phenotype and
RT a case of an unusual vulvar cancer.";
RL Hum. Mutat. 11:413-414(1998).
RN [40]
RP VARIANTS ALA-324 AND ARG-1367.
RX PubMed=10069711;
RX DOI=10.1002/(sici)1096-8628(19990219)82:5<399::aid-ajmg8>3.0.co;2-r;
RA Castro E., Ogburn C.E., Hunt K.E., Tilvis R., Louhija J., Penttinen R.,
RA Erkkola R., Panduro A., Riestra R., Piussan C., Deeb S.S., Wang L.,
RA 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 of
RT Finnish centenarians.";
RL Am. J. Med. Genet. 82:399-403(1999).
RN [41]
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 [42]
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., Rubin C.D.,
RA Chen D.-F., Yang C.-C., Juch H., Dorn T., Spiegel R., Oral E.A., Abid M.,
RA Battisti C., Lucci-Cordisco E., Neri G., Steed E.H., Kidd A., Isley W.,
RA Showalter D., Vittone J.L., Konstantinow A., Ring J., Meyer P.,
RA Wenger S.L., Herbay A.V., Wollina U., Schuelke M., Huizenga C.R.,
RA Leistritz D.F., Martin G.M., Mian I.S., Oshima J.;
RT "The spectrum of WRN mutations in Werner syndrome patients.";
RL Hum. Mutat. 27:558-567(2006).
RN [43]
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., Buckhaults P.,
RA Farrell C., Meeh P., Markowitz S.D., Willis J., Dawson D., Willson J.K.V.,
RA Gazdar A.F., Hartigan J., Wu L., Liu C., Parmigiani G., Park B.H.,
RA Bachman K.E., Papadopoulos N., Vogelstein B., Kinzler K.W.,
RA Velculescu V.E.;
RT "The consensus coding sequences of human breast and colorectal cancers.";
RL Science 314:268-274(2006).
RN [44]
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., Heath S.,
RA Shannon W.D., Nagarajan R., Walter M.J., Link D.C., Graubert T.A.,
RA 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 towards
CC double-stranded DNA with a 5'-overhang. Has no nuclease activity
CC towards single-stranded DNA or blunt-ended double-stranded DNA. Binds
CC preferentially to DNA substrates containing alternate secondary
CC structures, such as replication forks and Holliday junctions. May play
CC an important role in the dissociation of joint DNA molecules that can
CC arise as products of homologous recombination, at stalled replication
CC forks or during DNA repair. Alleviates stalling of DNA polymerases at
CC the site of DNA lesions. Important for genomic integrity. Plays a role
CC in the formation of DNA replication focal centers; stably associates
CC with foci elements generating binding sites for RP-A (By similarity).
CC Plays a role in double-strand break repair after gamma-irradiation.
CC {ECO:0000250|UniProtKB:O09053, 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, ECO:0000269|PubMed:27063109}.
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 (PubMed:11863428, PubMed:18596042,
CC PubMed:20159463). May exist as homodimer, homotrimer, homotetramer
CC and/or homohexamer (PubMed:11863428, PubMed:18596042, PubMed:20159463).
CC Homotetramer, or homohexamer, when bound to DNA (PubMed:11863428,
CC PubMed:18596042, PubMed:20159463). Interacts via its N-terminal domain
CC with WRNIP1 (By similarity). Interacts with EXO1, PCNA and SUPV3L1
CC (PubMed:12704184, PubMed:17961633). Interacts with PML (isoform PML-4)
CC (PubMed:21639834). Interacts (via KBM motif) with XRCC5 and XRCC6;
CC promoting recruitment to DNA damage sites (PubMed:27063109). Interacts
CC with RECQL5; this interaction stimulates WRN helicase activity on DNA
CC fork duplexes (PubMed:23180761). {ECO:0000250|UniProtKB:O09053,
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 ECO:0000269|PubMed:23180761, ECO:0000269|PubMed:27063109}.
CC -!- INTERACTION:
CC Q14191; P54132: BLM; NbExp=9; IntAct=EBI-368417, EBI-621372;
CC Q14191; P45973: CBX5; NbExp=3; IntAct=EBI-368417, EBI-78219;
CC Q14191; P39748: FEN1; NbExp=9; IntAct=EBI-368417, EBI-707816;
CC Q14191; P09874: PARP1; NbExp=8; IntAct=EBI-368417, EBI-355676;
CC Q14191; P43351: RAD52; NbExp=9; IntAct=EBI-368417, EBI-706448;
CC Q14191; P27694: RPA1; NbExp=9; IntAct=EBI-368417, EBI-621389;
CC Q14191; Q96EB6: SIRT1; NbExp=9; IntAct=EBI-368417, EBI-1802965;
CC Q14191; Q15554: TERF2; NbExp=8; IntAct=EBI-368417, EBI-706637;
CC Q14191; P04637: TP53; NbExp=5; IntAct=EBI-368417, EBI-366083;
CC Q14191; P12956: XRCC6; NbExp=6; IntAct=EBI-368417, EBI-353208;
CC -!- SUBCELLULAR LOCATION: Nucleus, nucleolus {ECO:0000269|PubMed:23180761,
CC ECO:0000269|PubMed:9618508}. Nucleus {ECO:0000269|PubMed:17563354,
CC ECO:0000269|PubMed:19652551, ECO:0000269|PubMed:23180761}. Nucleus,
CC nucleoplasm {ECO:0000269|PubMed:21639834}. Chromosome
CC {ECO:0000269|PubMed:27063109}. Note=Gamma-irradiation leads to its
CC translocation from nucleoli to nucleoplasm and PML regulates the
CC irradiation-induced WRN relocation (PubMed:21639834). Localizes to DNA
CC damage sites (PubMed:27063109). {ECO:0000269|PubMed:21639834,
CC ECO:0000269|PubMed:27063109}.
CC -!- DOMAIN: The KBM 2 (Ku-binding motif 2) and XLM (XLF-like motif) mediate
CC cooperative interaction with XRCC5/Ku80 and XRCC6/Ku70 and recruitment
CC to DNA damage sites. {ECO:0000269|PubMed:27063109}.
CC -!- PTM: Phosphorylated by PRKDC. {ECO:0000269|PubMed:11889123}.
CC -!- DISEASE: Werner syndrome (WRN) [MIM:277700]: A rare autosomal recessive
CC progeroid syndrome characterized by the premature onset of multiple
CC age-related disorders, including atherosclerosis, cancer, non-insulin-
CC dependent diabetes mellitus, ocular cataracts and osteoporosis. The
CC major cause of death, at a median age of 47, is myocardial infarction.
CC {ECO:0000269|PubMed:16673358}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- DISEASE: Colorectal cancer (CRC) [MIM:114500]: A complex disease
CC characterized by malignant lesions arising from the inner wall of the
CC large intestine (the colon) and the rectum. Genetic alterations are
CC often associated with progression from premalignant lesion (adenoma) to
CC invasive adenocarcinoma. Risk factors for cancer of the colon and
CC rectum include colon polyps, long-standing ulcerative colitis, and
CC genetic family history. {ECO:0000305|PubMed:24308539,
CC ECO:0000305|PubMed:9989816}. Note=The disease may be caused by variants
CC affecting the gene 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 and
CC Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/WRNID284.html";
CC -!- WEB RESOURCE: Name=NIEHS-SNPs;
CC URL="http://egp.gs.washington.edu/data/wrn/";
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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 PDB; 6TYV; X-ray; 1.93 A; B=8-23.
DR PDB; 6YHR; X-ray; 2.20 A; A=517-1093.
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 PDBsum; 6TYV; -.
DR PDBsum; 6YHR; -.
DR AlphaFoldDB; Q14191; -.
DR BMRB; Q14191; -.
DR SMR; Q14191; -.
DR BioGRID; 113323; 109.
DR CORUM; Q14191; -.
DR DIP; DIP-31380N; -.
DR ELM; Q14191; -.
DR IntAct; Q14191; 42.
DR MINT; Q14191; -.
DR STRING; 9606.ENSP00000298139; -.
DR BindingDB; Q14191; -.
DR ChEMBL; CHEMBL2146312; -.
DR GlyGen; Q14191; 1 site, 1 O-linked glycan (1 site).
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 ABCD; Q14191; 1 sequenced antibody.
DR Antibodypedia; 10619; 303 antibodies from 40 providers.
DR DNASU; 7486; -.
DR Ensembl; ENST00000298139.7; ENSP00000298139.5; ENSG00000165392.11.
DR GeneID; 7486; -.
DR KEGG; hsa:7486; -.
DR MANE-Select; ENST00000298139.7; ENSP00000298139.5; NM_000553.6; NP_000544.2.
DR UCSC; uc003xio.5; human.
DR CTD; 7486; -.
DR DisGeNET; 7486; -.
DR GeneCards; WRN; -.
DR GeneReviews; WRN; -.
DR HGNC; HGNC:12791; WRN.
DR HPA; ENSG00000165392; Low tissue specificity.
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 VEuPathDB; HostDB:ENSG00000165392; -.
DR eggNOG; KOG0351; Eukaryota.
DR eggNOG; KOG4373; Eukaryota.
DR GeneTree; ENSGT00940000159168; -.
DR HOGENOM; CLU_001103_11_1_1; -.
DR InParanoid; Q14191; -.
DR OMA; TSQDFGP; -.
DR OrthoDB; 445763at2759; -.
DR PhylomeDB; Q14191; -.
DR TreeFam; TF312852; -.
DR BRENDA; 3.6.4.12; 2681.
DR PathwayCommons; Q14191; -.
DR Reactome; R-HSA-174414; Processive synthesis on the C-strand of the telomere.
DR Reactome; R-HSA-174437; Removal of the Flap Intermediate from the C-strand.
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 Reactome; R-HSA-9701192; Defective HDR through Homologous Recombination (HRR) due to BRCA1 loss-of-function.
DR Reactome; R-HSA-9704331; Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA1 binding function.
DR Reactome; R-HSA-9704646; Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA2/RAD51/RAD51C binding function.
DR Reactome; R-HSA-9709570; Impaired BRCA2 binding to RAD51.
DR Reactome; R-HSA-9709603; Impaired BRCA2 binding to PALB2.
DR SignaLink; Q14191; -.
DR SIGNOR; Q14191; -.
DR BioGRID-ORCS; 7486; 53 hits in 1080 CRISPR screens.
DR ChiTaRS; WRN; human.
DR EvolutionaryTrace; Q14191; -.
DR GeneWiki; Werner_syndrome_ATP-dependent_helicase; -.
DR GenomeRNAi; 7486; -.
DR Pharos; Q14191; Tbio.
DR PRO; PR:Q14191; -.
DR Proteomes; UP000005640; Chromosome 8.
DR RNAct; Q14191; protein.
DR Bgee; ENSG00000165392; Expressed in calcaneal tendon and 163 other tissues.
DR ExpressionAtlas; Q14191; baseline and differential.
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:ATP hydrolysis 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: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: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:0090398; P:cellular senescence; IMP:GO_Central.
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; IBA:GO_Central.
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:0031297; P:replication fork processing; IDA:UniProtKB.
DR GO; GO:0090399; P:replicative senescence; 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:0032201; P:telomere maintenance via semi-conservative replication; TAS:Reactome.
DR GO; GO:0061820; P:telomeric D-loop disassembly; IDA:BHF-UCL.
DR Gene3D; 1.10.10.10; -; 1.
DR Gene3D; 1.10.150.80; -; 1.
DR Gene3D; 3.30.420.10; -; 1.
DR Gene3D; 3.40.50.300; -; 2.
DR IDEAL; IID00246; -.
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; IPR044876; HRDC_dom_sf.
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; Chromosome;
KW Direct protein sequencing; Disease variant; DNA damage; DNA repair;
KW DNA-binding; Exonuclease; Helicase; Hydrolase; Isopeptide bond; Magnesium;
KW Metal-binding; Multifunctional enzyme; Nuclease; Nucleotide-binding;
KW Nucleus; Phosphoprotein; Reference proteome; Repeat; Ubl conjugation; Zinc.
FT INIT_MET 1
FT /note="Removed"
FT /evidence="ECO:0007744|PubMed:22814378"
FT CHAIN 2..1432
FT /note="Bifunctional 3'-5' exonuclease/ATP-dependent
FT helicase WRN"
FT /id="PRO_0000205045"
FT DOMAIN 60..228
FT /note="3'-5' exonuclease"
FT REPEAT 424..450
FT /note="1"
FT /evidence="ECO:0000269|PubMed:10049920"
FT REPEAT 451..477
FT /note="2"
FT /evidence="ECO:0000269|PubMed:10049920"
FT DOMAIN 558..724
FT /note="Helicase ATP-binding"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00541"
FT DOMAIN 749..899
FT /note="Helicase C-terminal"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00542"
FT DOMAIN 1150..1229
FT /note="HRDC"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00328"
FT REGION 2..277
FT /note="Interaction with WRNIP1"
FT /evidence="ECO:0000250|UniProtKB:O09053"
FT REGION 424..477
FT /note="2 X 27 AA tandem repeats of H-L-S-P-N-D-N-E-N-D-T-S-
FT Y-V-I-E-S-D-E-D-L-E-M-E-M-L-K"
FT REGION 498..529
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 987..993
FT /note="Interaction with DNA"
FT /evidence="ECO:0000269|PubMed:20159463"
FT MOTIF 11..23
FT /note="KBM 1"
FT /evidence="ECO:0000305|PubMed:27063109"
FT MOTIF 668..671
FT /note="DEAH box"
FT MOTIF 1403..1412
FT /note="KBM 2"
FT /evidence="ECO:0000305|PubMed:27063109"
FT MOTIF 1419..1432
FT /note="XLM"
FT /evidence="ECO:0000305|PubMed:27063109"
FT COMPBIAS 507..528
FT /note="Acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT BINDING 82
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT /ligand_label="1"
FT /ligand_note="catalytic"
FT /evidence="ECO:0000269|PubMed:16622405,
FT ECO:0007744|PDB:2FBV, ECO:0007744|PDB:2FBX,
FT ECO:0007744|PDB:2FC0"
FT BINDING 82
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT /ligand_label="2"
FT /ligand_note="catalytic"
FT /evidence="ECO:0000269|PubMed:16622405,
FT ECO:0007744|PDB:2FBV, ECO:0007744|PDB:2FBX,
FT ECO:0007744|PDB:2FC0"
FT BINDING 84
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT /ligand_label="1"
FT /ligand_note="catalytic"
FT /evidence="ECO:0000269|PubMed:16622405,
FT ECO:0007744|PDB:2FBV, ECO:0007744|PDB:2FBX,
FT ECO:0007744|PDB:2FC0"
FT BINDING 216
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT /ligand_label="1"
FT /ligand_note="catalytic"
FT /evidence="ECO:0000269|PubMed:16622405,
FT ECO:0007744|PDB:2FBV, ECO:0007744|PDB:2FBX,
FT ECO:0007744|PDB:2FC0"
FT BINDING 571..578
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00541"
FT SITE 145
FT /note="Interaction with DNA"
FT /evidence="ECO:0000305|PubMed:20159463"
FT SITE 1037
FT /note="Interaction with DNA"
FT /evidence="ECO:0000305|PubMed:20159463"
FT MOD_RES 2
FT /note="N-acetylserine"
FT /evidence="ECO:0007744|PubMed:22814378"
FT MOD_RES 426
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:19690332"
FT MOD_RES 440
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:18669648,
FT ECO:0007744|PubMed:19690332"
FT MOD_RES 453
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:19690332"
FT MOD_RES 467
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:18669648,
FT ECO:0007744|PubMed:19690332"
FT MOD_RES 478
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT MOD_RES 1133
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21406692,
FT ECO:0007744|PubMed:23186163"
FT MOD_RES 1400
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT CROSSLNK 154
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO2)"
FT /evidence="ECO:0007744|PubMed:28112733"
FT CROSSLNK 241
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO2)"
FT /evidence="ECO:0007744|PubMed:28112733"
FT CROSSLNK 252
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO2)"
FT /evidence="ECO:0007744|PubMed:28112733"
FT VARIANT 32
FT /note="K -> R (in dbSNP:rs34477820)"
FT /evidence="ECO:0000269|PubMed:11161804"
FT /id="VAR_017453"
FT VARIANT 92
FT /note="G -> V (in a colorectal cancer sample; somatic
FT mutation)"
FT /evidence="ECO:0000269|PubMed:16959974"
FT /id="VAR_036318"
FT VARIANT 114
FT /note="V -> I (no effect on exonuclease activity;
FT dbSNP:rs2230009)"
FT /evidence="ECO:0000269|PubMed:11161804,
FT ECO:0000269|PubMed:16622405, ECO:0000269|Ref.4"
FT /id="VAR_017454"
FT VARIANT 125
FT /note="K -> N (in WRN; dbSNP:rs387906337)"
FT /evidence="ECO:0000269|PubMed:16673358"
FT /id="VAR_026588"
FT VARIANT 135
FT /note="K -> E (in WRN; dbSNP:rs267607008)"
FT /evidence="ECO:0000269|PubMed:16673358"
FT /id="VAR_026589"
FT VARIANT 172
FT /note="T -> P (no effect on exonuclease activity;
FT dbSNP:rs367991517)"
FT /evidence="ECO:0000269|PubMed:11161804,
FT ECO:0000269|PubMed:16622405"
FT /id="VAR_017455"
FT VARIANT 240
FT /note="N -> K (in dbSNP:rs148229804)"
FT /evidence="ECO:0000269|PubMed:11161804"
FT /id="VAR_017456"
FT VARIANT 324
FT /note="T -> A (in dbSNP:rs1800390)"
FT /evidence="ECO:0000269|PubMed:10069711"
FT /id="VAR_006904"
FT VARIANT 329
FT /note="Q -> R (in dbSNP:rs4987237)"
FT /id="VAR_020450"
FT VARIANT 343
FT /note="E -> K (in dbSNP:rs11574222)"
FT /evidence="ECO:0000269|Ref.4"
FT /id="VAR_018941"
FT VARIANT 383
FT /note="L -> F (in dbSNP:rs4987238)"
FT /id="VAR_020451"
FT VARIANT 383
FT /note="L -> W"
FT /evidence="ECO:0000269|PubMed:11161804"
FT /id="VAR_017457"
FT VARIANT 387
FT /note="M -> I (in dbSNP:rs1800391)"
FT /evidence="ECO:0000269|PubMed:10206685,
FT ECO:0000269|PubMed:11161804, ECO:0000269|PubMed:9450180,
FT ECO:0000269|Ref.4"
FT /id="VAR_006905"
FT VARIANT 533
FT /note="N -> S (in dbSNP:rs11574240)"
FT /evidence="ECO:0000269|Ref.4"
FT /id="VAR_018942"
FT VARIANT 612
FT /note="S -> C (in dbSNP:rs11574250)"
FT /evidence="ECO:0000269|Ref.4"
FT /id="VAR_018943"
FT VARIANT 708
FT /note="S -> F (in dbSNP:rs11574289)"
FT /evidence="ECO:0000269|Ref.4"
FT /id="VAR_018944"
FT VARIANT 711
FT /note="R -> W (in dbSNP:rs34560788)"
FT /id="VAR_057124"
FT VARIANT 724
FT /note="Q -> L"
FT /evidence="ECO:0000269|PubMed:11161804"
FT /id="VAR_017458"
FT VARIANT 834
FT /note="R -> C (in dbSNP:rs3087425)"
FT /evidence="ECO:0000269|Ref.4"
FT /id="VAR_014913"
FT VARIANT 912
FT /note="I -> S (in dbSNP:rs11574323)"
FT /evidence="ECO:0000269|Ref.4"
FT /id="VAR_018945"
FT VARIANT 1074
FT /note="L -> F (in dbSNP:rs1801195)"
FT /evidence="ECO:0000269|PubMed:11161804,
FT ECO:0000269|PubMed:16723399, ECO:0000269|PubMed:8602509,
FT ECO:0000269|PubMed:9450180, ECO:0000269|Ref.3"
FT /id="VAR_007903"
FT VARIANT 1079
FT /note="S -> L (in dbSNP:rs3087414)"
FT /evidence="ECO:0000269|Ref.4"
FT /id="VAR_014914"
FT VARIANT 1133
FT /note="S -> A (in dbSNP:rs11574358)"
FT /evidence="ECO:0000269|Ref.4"
FT /id="VAR_018946"
FT VARIANT 1141
FT /note="S -> L (in dbSNP:rs139323683)"
FT /evidence="ECO:0000269|PubMed:18987736"
FT /id="VAR_054162"
FT VARIANT 1269
FT /note="K -> E (in dbSNP:rs746648510)"
FT /evidence="ECO:0000269|PubMed:11161804"
FT /id="VAR_017459"
FT VARIANT 1339
FT /note="V -> I (in dbSNP:rs11574395)"
FT /evidence="ECO:0000269|Ref.4"
FT /id="VAR_018947"
FT VARIANT 1367
FT /note="C -> R (associated with a higher risk of myocardial
FT infarction; dbSNP:rs1346044)"
FT /evidence="ECO:0000269|PubMed:10069711,
FT ECO:0000269|PubMed:11161804, ECO:0000269|PubMed:9021029,
FT ECO:0000269|Ref.4"
FT /id="VAR_006906"
FT MUTAGEN 18
FT /note="W->G: Abolished interaction with XRCC5 and XRCC6."
FT /evidence="ECO:0000269|PubMed:27063109"
FT MUTAGEN 84
FT /note="E->A: Abolishes exonuclease activity."
FT /evidence="ECO:0000269|PubMed:11863428,
FT ECO:0000269|PubMed:16622405, ECO:0000269|PubMed:27063109"
FT MUTAGEN 88
FT /note="L->A: No effect on exonuclease activity."
FT MUTAGEN 145
FT /note="W->A: Reduces exonuclease activity."
FT /evidence="ECO:0000269|PubMed:16622405"
FT MUTAGEN 212
FT /note="Y->F: Strongly reduces exonuclease activity."
FT /evidence="ECO:0000269|PubMed:16622405"
FT MUTAGEN 987
FT /note="R->A: Reduces affinity for DNA about 8-fold. Loss of
FT DNA binding; when associated with A-993."
FT /evidence="ECO:0000269|PubMed:20159463"
FT MUTAGEN 989
FT /note="S->A: Reduces affinity for DNA about 4-fold."
FT /evidence="ECO:0000269|PubMed:20159463"
FT MUTAGEN 993
FT /note="R->A: Reduces affinity for DNA about 20-fold. Loss
FT of DNA binding; when associated with A-987."
FT /evidence="ECO:0000269|PubMed:20159463"
FT MUTAGEN 993
FT /note="R->E: Loss of DNA binding."
FT /evidence="ECO:0000269|PubMed:20159463"
FT MUTAGEN 1037
FT /note="F->A: Reduces affinity for DNA about 8-fold."
FT /evidence="ECO:0000269|PubMed:20159463"
FT MUTAGEN 1038
FT /note="M->A: Reduces affinity for DNA about 4-fold."
FT /evidence="ECO:0000269|PubMed:20159463"
FT HELIX 17..19
FT /evidence="ECO:0007829|PDB:6TYV"
FT HELIX 39..41
FT /evidence="ECO:0007829|PDB:2FBY"
FT STRAND 51..56
FT /evidence="ECO:0007829|PDB:2FBY"
FT HELIX 59..72
FT /evidence="ECO:0007829|PDB:2FBY"
FT STRAND 78..84
FT /evidence="ECO:0007829|PDB:2FBY"
FT STRAND 99..105
FT /evidence="ECO:0007829|PDB:2FBY"
FT STRAND 108..112
FT /evidence="ECO:0007829|PDB:2FBY"
FT HELIX 114..116
FT /evidence="ECO:0007829|PDB:2FBY"
FT STRAND 117..119
FT /evidence="ECO:0007829|PDB:2FBY"
FT HELIX 122..128
FT /evidence="ECO:0007829|PDB:2FBY"
FT STRAND 133..139
FT /evidence="ECO:0007829|PDB:2FBY"
FT HELIX 140..151
FT /evidence="ECO:0007829|PDB:2FBY"
FT STRAND 157..160
FT /evidence="ECO:0007829|PDB:2FBY"
FT HELIX 161..169
FT /evidence="ECO:0007829|PDB:2FBY"
FT HELIX 177..185
FT /evidence="ECO:0007829|PDB:2FBY"
FT HELIX 193..196
FT /evidence="ECO:0007829|PDB:2FBY"
FT STRAND 202..204
FT /evidence="ECO:0007829|PDB:2FBY"
FT HELIX 207..228
FT /evidence="ECO:0007829|PDB:2FBY"
FT HELIX 534..544
FT /evidence="ECO:0007829|PDB:6YHR"
FT HELIX 551..561
FT /evidence="ECO:0007829|PDB:6YHR"
FT STRAND 567..570
FT /evidence="ECO:0007829|PDB:6YHR"
FT HELIX 579..588
FT /evidence="ECO:0007829|PDB:6YHR"
FT STRAND 590..595
FT /evidence="ECO:0007829|PDB:6YHR"
FT HELIX 599..610
FT /evidence="ECO:0007829|PDB:6YHR"
FT TURN 611..613
FT /evidence="ECO:0007829|PDB:6YHR"
FT STRAND 616..618
FT /evidence="ECO:0007829|PDB:6YHR"
FT HELIX 625..632
FT /evidence="ECO:0007829|PDB:6YHR"
FT STRAND 637..641
FT /evidence="ECO:0007829|PDB:6YHR"
FT HELIX 643..648
FT /evidence="ECO:0007829|PDB:6YHR"
FT HELIX 650..659
FT /evidence="ECO:0007829|PDB:6YHR"
FT STRAND 662..667
FT /evidence="ECO:0007829|PDB:6YHR"
FT HELIX 670..673
FT /evidence="ECO:0007829|PDB:6YHR"
FT STRAND 677..679
FT /evidence="ECO:0007829|PDB:6YHR"
FT HELIX 682..689
FT /evidence="ECO:0007829|PDB:6YHR"
FT HELIX 690..693
FT /evidence="ECO:0007829|PDB:6YHR"
FT STRAND 699..705
FT /evidence="ECO:0007829|PDB:6YHR"
FT HELIX 708..718
FT /evidence="ECO:0007829|PDB:6YHR"
FT STRAND 724..727
FT /evidence="ECO:0007829|PDB:6YHR"
FT STRAND 735..741
FT /evidence="ECO:0007829|PDB:6YHR"
FT HELIX 746..750
FT /evidence="ECO:0007829|PDB:6YHR"
FT HELIX 751..753
FT /evidence="ECO:0007829|PDB:6YHR"
FT STRAND 754..757
FT /evidence="ECO:0007829|PDB:6YHR"
FT STRAND 760..765
FT /evidence="ECO:0007829|PDB:6YHR"
FT STRAND 767..770
FT /evidence="ECO:0007829|PDB:6YHR"
FT HELIX 774..786
FT /evidence="ECO:0007829|PDB:6YHR"
FT STRAND 791..794
FT /evidence="ECO:0007829|PDB:6YHR"
FT HELIX 800..811
FT /evidence="ECO:0007829|PDB:6YHR"
FT STRAND 814..821
FT /evidence="ECO:0007829|PDB:6YHR"
FT HELIX 826..828
FT /evidence="ECO:0007829|PDB:6YHR"
FT STRAND 835..840
FT /evidence="ECO:0007829|PDB:6YHR"
FT HELIX 845..852
FT /evidence="ECO:0007829|PDB:6YHR"
FT STRAND 862..868
FT /evidence="ECO:0007829|PDB:6YHR"
FT HELIX 873..875
FT /evidence="ECO:0007829|PDB:6YHR"
FT HELIX 877..880
FT /evidence="ECO:0007829|PDB:6YHR"
FT HELIX 886..904
FT /evidence="ECO:0007829|PDB:6YHR"
FT HELIX 909..918
FT /evidence="ECO:0007829|PDB:6YHR"
FT TURN 928..931
FT /evidence="ECO:0007829|PDB:6YHR"
FT TURN 933..935
FT /evidence="ECO:0007829|PDB:6YHR"
FT HELIX 937..944
FT /evidence="ECO:0007829|PDB:6YHR"
FT STRAND 956..958
FT /evidence="ECO:0007829|PDB:6YHR"
FT HELIX 960..972
FT /evidence="ECO:0007829|PDB:3AAF"
FT TURN 973..975
FT /evidence="ECO:0007829|PDB:3AAF"
FT HELIX 980..986
FT /evidence="ECO:0007829|PDB:3AAF"
FT HELIX 996..1000
FT /evidence="ECO:0007829|PDB:3AAF"
FT TURN 1002..1009
FT /evidence="ECO:0007829|PDB:3AAF"
FT HELIX 1012..1024
FT /evidence="ECO:0007829|PDB:3AAF"
FT STRAND 1027..1032
FT /evidence="ECO:0007829|PDB:3AAF"
FT TURN 1036..1038
FT /evidence="ECO:0007829|PDB:2AXL"
FT STRAND 1039..1043
FT /evidence="ECO:0007829|PDB:3AAF"
FT HELIX 1045..1054
FT /evidence="ECO:0007829|PDB:3AAF"
FT STRAND 1062..1064
FT /evidence="ECO:0007829|PDB:6YHR"
FT TURN 1067..1069
FT /evidence="ECO:0007829|PDB:6YHR"
FT HELIX 1147..1171
FT /evidence="ECO:0007829|PDB:2E1F"
FT HELIX 1175..1178
FT /evidence="ECO:0007829|PDB:2E1F"
FT HELIX 1181..1190
FT /evidence="ECO:0007829|PDB:2E1F"
FT HELIX 1195..1198
FT /evidence="ECO:0007829|PDB:2E1F"
FT STRAND 1201..1203
FT /evidence="ECO:0007829|PDB:2DGZ"
FT HELIX 1206..1211
FT /evidence="ECO:0007829|PDB:2E1F"
FT HELIX 1213..1225
FT /evidence="ECO:0007829|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
