Izvorni kôd stranice WRN

{{Infokutija gen}}
'''[[ATP]]-ovisna [[helikaza]] Wernerovog sindroma''', znana i kao  '''DNK-helikazno rekvoliki tip 3''',  je [[enzim]] koji je kod [[ljudi]] [[kodon|kodiran]] [[gen]]om '''WRN'''. WRN je član porodice  [[RecQ-helikaza]].<ref name=Monnat/> Enzimi helikaze općenito se odmotavaju i odvajaju dvolančane [[DNK]]. Ove aktivnosti su neophodne prije nego što se DNK može kopirati u pripremi za [[ćelijska dioba|diobu ćelija]] ([[replikacija DNK]]). Helikazni enzimi su također kritični za stvaranje nacrta gena za proizvodnju proteina, proces koji se naziva [[Transkripcija (genetika)|transkripcija]]. Dodatni dokazi ukazuju na to da Wernerov protein ima ključnu ulogu u [[Popravka DNK|popravljanju DNK]]. Sve u svemu, ovaj protein pomaže u održavanju strukture i integriteta individualne DNK.

WRN gen nalazi se na kratkom (p) kraku [[hromosom 8|hromosoma 8]], između pozicija 12 i 11.2, od [[bazni par|bp]] 31,010.319 do bp 31,150.818. Helikazni enzimi općenito odmotavaju i razdvajaju dvolančane [[DNK]]. Ove aktivnosti su neophodne prije nego što se DNK može kopirati u pripremi za diobu ćelija ([[replikacija DNK]]). Enzimi helikaze su takođe kritični za stvaranje nacrta gena za proizvodnju proteina, procesa koji se naziva [[Transkripcija (genetika)|transkripcija]]. Dodatni dokazi ukazuju na to da Wernerov protein igra ključnu ulogu u [[popravak DNK|popravljanju DNK]]. Sve u svemu, ovaj protein pomaže u održavanju strukture i integriteta DNK osobe.

WRN gen se nalazi na kratkom (p) kraku [[hromosom 8|hromosoma 8]] između pozicija 12 i 11.2, od [[bazni par|bp]] 31,010.319 do bp 31,150.818.
==Aminokiselinska sekvenca==
Dužina [[polipeptid]]nog lanca je  1.432 [[aminokiseline]], а [[molekularna masa|molekulska težina]]  162.461 [[dalton (jedinica)|Da]].<ref name="UniProt">{{cite web|url=http://www.uniprot.org/uniprot/Q14191#sequences |title=UniProt, Q14191 |language=en |access-date=21. 9. 2021}}</ref>
<table  style="font-family:monospace;">
<tr style="text-align:right;"><th>10</th><th></th><th>20</th><th></th><th>30</th><th></th><th>40</th><th></th><th>50</th></tr>
<tr style="background-color: #eee;"><td>MSEKKLETTA</td><td style="background-color: #f9f9f9;"></td><td>QQRKCPEWMN</td><td style="background-color: #f9f9f9;"></td><td>VQNKRCAVEE</td><td style="background-color: #f9f9f9;"></td><td>RKACVRKSVF</td><td style="background-color: #f9f9f9;"></td><td>EDDLPFLEFT</td></tr>
<tr style="background-color: #eee;"><td>GSIVYSYDAS</td><td style="background-color: #f9f9f9;"></td><td>DCSFLSEDIS</td><td style="background-color: #f9f9f9;"></td><td>MSLSDGDVVG</td><td style="background-color: #f9f9f9;"></td><td>FDMEWPPLYN</td><td style="background-color: #f9f9f9;"></td><td>RGKLGKVALI</td></tr>
<tr style="background-color: #eee;"><td>QLCVSESKCY</td><td style="background-color: #f9f9f9;"></td><td>LFHVSSMSVF</td><td style="background-color: #f9f9f9;"></td><td>PQGLKMLLEN</td><td style="background-color: #f9f9f9;"></td><td>KAVKKAGVGI</td><td style="background-color: #f9f9f9;"></td><td>EGDQWKLLRD</td></tr>
<tr style="background-color: #eee;"><td>FDIKLKNFVE</td><td style="background-color: #f9f9f9;"></td><td>LTDVANKKLK</td><td style="background-color: #f9f9f9;"></td><td>CTETWSLNSL</td><td style="background-color: #f9f9f9;"></td><td>VKHLLGKQLL</td><td style="background-color: #f9f9f9;"></td><td>KDKSIRCSNW</td></tr>
<tr style="background-color: #eee;"><td>SKFPLTEDQK</td><td style="background-color: #f9f9f9;"></td><td>LYAATDAYAG</td><td style="background-color: #f9f9f9;"></td><td>FIIYRNLEIL</td><td style="background-color: #f9f9f9;"></td><td>DDTVQRFAIN</td><td style="background-color: #f9f9f9;"></td><td>KEEEILLSDM</td></tr>
<tr style="background-color: #eee;"><td>NKQLTSISEE</td><td style="background-color: #f9f9f9;"></td><td>VMDLAKHLPH</td><td style="background-color: #f9f9f9;"></td><td>AFSKLENPRR</td><td style="background-color: #f9f9f9;"></td><td>VSILLKDISE</td><td style="background-color: #f9f9f9;"></td><td>NLYSLRRMII</td></tr>
<tr style="background-color: #eee;"><td>GSTNIETELR</td><td style="background-color: #f9f9f9;"></td><td>PSNNLNLLSF</td><td style="background-color: #f9f9f9;"></td><td>EDSTTGGVQQ</td><td style="background-color: #f9f9f9;"></td><td>KQIREHEVLI</td><td style="background-color: #f9f9f9;"></td><td>HVEDETWDPT</td></tr>
<tr style="background-color: #eee;"><td>LDHLAKHDGE</td><td style="background-color: #f9f9f9;"></td><td>DVLGNKVERK</td><td style="background-color: #f9f9f9;"></td><td>EDGFEDGVED</td><td style="background-color: #f9f9f9;"></td><td>NKLKENMERA</td><td style="background-color: #f9f9f9;"></td><td>CLMSLDITEH</td></tr>
<tr style="background-color: #eee;"><td>ELQILEQQSQ</td><td style="background-color: #f9f9f9;"></td><td>EEYLSDIAYK</td><td style="background-color: #f9f9f9;"></td><td>STEHLSPNDN</td><td style="background-color: #f9f9f9;"></td><td>ENDTSYVIES</td><td style="background-color: #f9f9f9;"></td><td>DEDLEMEMLK</td></tr>
<tr style="background-color: #eee;"><td>HLSPNDNEND</td><td style="background-color: #f9f9f9;"></td><td>TSYVIESDED</td><td style="background-color: #f9f9f9;"></td><td>LEMEMLKSLE</td><td style="background-color: #f9f9f9;"></td><td>NLNSGTVEPT</td><td style="background-color: #f9f9f9;"></td><td>HSKCLKMERN</td></tr>
<tr style="background-color: #eee;"><td>LGLPTKEEEE</td><td style="background-color: #f9f9f9;"></td><td>DDENEANEGE</td><td style="background-color: #f9f9f9;"></td><td>EDDDKDFLWP</td><td style="background-color: #f9f9f9;"></td><td>APNEEQVTCL</td><td style="background-color: #f9f9f9;"></td><td>KMYFGHSSFK</td></tr>
<tr style="background-color: #eee;"><td>PVQWKVIHSV</td><td style="background-color: #f9f9f9;"></td><td>LEERRDNVAV</td><td style="background-color: #f9f9f9;"></td><td>MATGYGKSLC</td><td style="background-color: #f9f9f9;"></td><td>FQYPPVYVGK</td><td style="background-color: #f9f9f9;"></td><td>IGLVISPLIS</td></tr>
<tr style="background-color: #eee;"><td>LMEDQVLQLK</td><td style="background-color: #f9f9f9;"></td><td>MSNIPACFLG</td><td style="background-color: #f9f9f9;"></td><td>SAQSENVLTD</td><td style="background-color: #f9f9f9;"></td><td>IKLGKYRIVY</td><td style="background-color: #f9f9f9;"></td><td>VTPEYCSGNM</td></tr>
<tr style="background-color: #eee;"><td>GLLQQLEADI</td><td style="background-color: #f9f9f9;"></td><td>GITLIAVDEA</td><td style="background-color: #f9f9f9;"></td><td>HCISEWGHDF</td><td style="background-color: #f9f9f9;"></td><td>RDSFRKLGSL</td><td style="background-color: #f9f9f9;"></td><td>KTALPMVPIV</td></tr>
<tr style="background-color: #eee;"><td>ALTATASSSI</td><td style="background-color: #f9f9f9;"></td><td>REDIVRCLNL</td><td style="background-color: #f9f9f9;"></td><td>RNPQITCTGF</td><td style="background-color: #f9f9f9;"></td><td>DRPNLYLEVR</td><td style="background-color: #f9f9f9;"></td><td>RKTGNILQDL</td></tr>
<tr style="background-color: #eee;"><td>QPFLVKTSSH</td><td style="background-color: #f9f9f9;"></td><td>WEFEGPTIIY</td><td style="background-color: #f9f9f9;"></td><td>CPSRKMTQQV</td><td style="background-color: #f9f9f9;"></td><td>TGELRKLNLS</td><td style="background-color: #f9f9f9;"></td><td>CGTYHAGMSF</td></tr>
<tr style="background-color: #eee;"><td>STRKDIHHRF</td><td style="background-color: #f9f9f9;"></td><td>VRDEIQCVIA</td><td style="background-color: #f9f9f9;"></td><td>TIAFGMGINK</td><td style="background-color: #f9f9f9;"></td><td>ADIRQVIHYG</td><td style="background-color: #f9f9f9;"></td><td>APKDMESYYQ</td></tr>
<tr style="background-color: #eee;"><td>EIGRAGRDGL</td><td style="background-color: #f9f9f9;"></td><td>QSSCHVLWAP</td><td style="background-color: #f9f9f9;"></td><td>ADINLNRHLL</td><td style="background-color: #f9f9f9;"></td><td>TEIRNEKFRL</td><td style="background-color: #f9f9f9;"></td><td>YKLKMMAKME</td></tr>
<tr style="background-color: #eee;"><td>KYLHSSRCRR</td><td style="background-color: #f9f9f9;"></td><td>QIILSHFEDK</td><td style="background-color: #f9f9f9;"></td><td>QVQKASLGIM</td><td style="background-color: #f9f9f9;"></td><td>GTEKCCDNCR</td><td style="background-color: #f9f9f9;"></td><td>SRLDHCYSMD</td></tr>
<tr style="background-color: #eee;"><td>DSEDTSWDFG</td><td style="background-color: #f9f9f9;"></td><td>PQAFKLLSAV</td><td style="background-color: #f9f9f9;"></td><td>DILGEKFGIG</td><td style="background-color: #f9f9f9;"></td><td>LPILFLRGSN</td><td style="background-color: #f9f9f9;"></td><td>SQRLADQYRR</td></tr>
<tr style="background-color: #eee;"><td>HSLFGTGKDQ</td><td style="background-color: #f9f9f9;"></td><td>TESWWKAFSR</td><td style="background-color: #f9f9f9;"></td><td>QLITEGFLVE</td><td style="background-color: #f9f9f9;"></td><td>VSRYNKFMKI</td><td style="background-color: #f9f9f9;"></td><td>CALTKKGRNW</td></tr>
<tr style="background-color: #eee;"><td>LHKANTESQS</td><td style="background-color: #f9f9f9;"></td><td>LILQANEELC</td><td style="background-color: #f9f9f9;"></td><td>PKKLLLPSSK</td><td style="background-color: #f9f9f9;"></td><td>TVSSGTKEHC</td><td style="background-color: #f9f9f9;"></td><td>YNQVPVELST</td></tr>
<tr style="background-color: #eee;"><td>EKKSNLEKLY</td><td style="background-color: #f9f9f9;"></td><td>SYKPCDKISS</td><td style="background-color: #f9f9f9;"></td><td>GSNISKKSIM</td><td style="background-color: #f9f9f9;"></td><td>VQSPEKAYSS</td><td style="background-color: #f9f9f9;"></td><td>SQPVISAQEQ</td></tr>
<tr style="background-color: #eee;"><td>ETQIVLYGKL</td><td style="background-color: #f9f9f9;"></td><td>VEARQKHANK</td><td style="background-color: #f9f9f9;"></td><td>MDVPPAILAT</td><td style="background-color: #f9f9f9;"></td><td>NKILVDMAKM</td><td style="background-color: #f9f9f9;"></td><td>RPTTVENVKR</td></tr>
<tr style="background-color: #eee;"><td>IDGVSEGKAA</td><td style="background-color: #f9f9f9;"></td><td>MLAPLLEVIK</td><td style="background-color: #f9f9f9;"></td><td>HFCQTNSVQT</td><td style="background-color: #f9f9f9;"></td><td>DLFSSTKPQE</td><td style="background-color: #f9f9f9;"></td><td>EQKTSLVAKN</td></tr>
<tr style="background-color: #eee;"><td>KICTLSQSMA</td><td style="background-color: #f9f9f9;"></td><td>ITYSLFQEKK</td><td style="background-color: #f9f9f9;"></td><td>MPLKSIAESR</td><td style="background-color: #f9f9f9;"></td><td>ILPLMTIGMH</td><td style="background-color: #f9f9f9;"></td><td>LSQAVKAGCP</td></tr>
<tr style="background-color: #eee;"><td>LDLERAGLTP</td><td style="background-color: #f9f9f9;"></td><td>EVQKIIADVI</td><td style="background-color: #f9f9f9;"></td><td>RNPPVNSDMS</td><td style="background-color: #f9f9f9;"></td><td>KISLIRMLVP</td><td style="background-color: #f9f9f9;"></td><td>ENIDTYLIHM</td></tr>
<tr style="background-color: #eee;"><td>AIEILKHGPD</td><td style="background-color: #f9f9f9;"></td><td>SGLQPSCDVN</td><td style="background-color: #f9f9f9;"></td><td>KRRCFPGSEE</td><td style="background-color: #f9f9f9;"></td><td>ICSSSKRSKE</td><td style="background-color: #f9f9f9;"></td><td>EVGINTETSS</td></tr>
<tr style="background-color: #eee;"><td>AERKRRLPVW</td><td style="background-color: #f9f9f9;"></td><td>FAKGSDTSKK</td><td style="background-color: #f9f9f9;"></td><td>LMDKTKRGGL</td><td style="background-color: #f9f9f9;"></td><td>FS</td></tr>
</table>
{{refbegin|3}}
'''C''': [[Cistein]]<br/>
'''D''': [[Asparaginska kiselina|Aspartat]]<br/>
'''E''': [[Glutaminska kiselina|Glutamat]]<br/>
'''F''': [[Fenilalanin]] <br/>
'''G''': [[Glicin]]<br/>
'''H''': [[Histidin]]<br/>
'''I''': [[Izoleucin]] <br/>
'''K''': [[Lizin]]<br/>
'''L''': [[Leucin]]<br/>
'''M''': [[Metionin]]<br/>
'''N''': [[Asparagin]]<br/>
'''P''': [[Prolin]]<br/>
'''Q''': [[Glutamin]]<br/>
'''R''': [[Arginin]]<br/>
'''S''': [[Serin]]<br/>
'''T''': [[Treonin]]<br/>
'''V''': [[Valin]]<br/>
:'''W''': [[Triptofan]]
'''Y''': [[Tirozin]]
{{refend}}

== Struktura i funkcija ==

WRN je član porodice [[helikaza RecQ]]. To je jedina [[helikaza]] RecQ koja sadrži 3 'do 5' [[egzonukleaza|egzonukleaznu]] aktivnost. Ove aktivnosti egzonukleaze uključuju razgradnju udubljenih 3' krajeva i započinjanje razgradnje [[DNK]] iz praznine u dsDNA. WRN je važan u [[popravak DNK|popravci]] dvolančanih prekida pomoću [[homologna rekombinacija|homologne rekombinacije]]<ref name="pmid12242278">{{cite journal |vauthors=Saintigny Y, Makienko K, Swanson C, Emond MJ, Monnat RJ |title=Homologous recombination resolution defect in werner syndrome |journal=Mol. Cell. Biol. |volume=22 |issue=20 |pages=6971–8 |year=2002 |pmid=12242278 |pmc=139822 |doi= 10.1128/mcb.22.20.6971-6978.2002}}</ref><ref name="pmid25122754">{{cite journal |vauthors=Sturzenegger A, Burdova K, Kanagaraj R, Levikova M, Pinto C, Cejka P, Janscak P |title=DNA2 cooperates with the WRN and BLM RecQ helicases to mediate long-range DNA end resection in human cells |journal=J. Biol. Chem. |volume=289 |issue=39 |pages=27314–26 |year=2014 |pmid=25122754 |pmc=4175362 |doi=10.1074/jbc.M114.578823 }}</ref> ili [[nehomologno spajanje krajeva|nehomolognog spajanja krajeva]],<ref name="pmid27922005">{{cite journal |vauthors=Shamanna RA, Lu H, de Freitas JK, Tian J, Croteau DL, Bohr VA |title=WRN regulates pathway choice between classical and alternative non-homologous end joining |journal=Nat Commun |volume=7 |pages=13785 |year=2016 |pmid=27922005 |pmc=5150655 |doi=10.1038/ncomms13785 }}</ref> sanacija oštećenja pojedinačnih nukleotida [[popravak DNK|popravkom ekscizije baze]],<ref name=Monnat>{{cite journal | author = Monnat RJ | title = Human RECQ helicases: roles in DNA metabolism, mutagenesis and cancer biology | journal = Semin. Cancer Biol. | volume = 20 | issue = 5 | pages = 329–39 |date=oktobar 2010  | pmid = 20934517 | pmc = 3040982 | doi = 10.1016/j.semcancer.2010.10.002 }}</ref><ref name="pmid17611195">{{cite journal |vauthors=Das A, Boldogh I, Lee JW, Harrigan JA, Hegde ML, Piotrowski J, de Souza Pinto N, Ramos W, Greenberg MM, Hazra TK, Mitra S, Bohr VA |title=The human Werner syndrome protein stimulates repair of oxidative DNA base damage by the DNA glycosylase NEIL1 |journal=J. Biol. Chem. |volume=282 |issue=36 |pages=26591–602 |year=2007 |pmid=17611195 |doi=10.1074/jbc.M703343200 |doi-access=free }}</ref><ref name="pmid22753033">{{cite journal |vauthors=Kanagaraj R, Parasuraman P, Mihaljevic B, van Loon B, Burdova K, König C, Furrer A, Bohr VA, Hübscher U, Janscak P |title=Involvement of Werner syndrome protein in MUTYH-mediated repair of oxidative DNA damage |journal=Nucleic Acids Res. |volume=40 |issue=17 |pages=8449–59 |year=2012 |pmid=22753033 |pmc=3458577 |doi=10.1093/nar/gks648 }}</ref> i efikasan je u oporavku pri zaustavljanju replikacije.<ref name="pmid21389352">{{cite journal |vauthors=Pichierri P, Ammazzalorso F, Bignami M, Franchitto A |title=The Werner syndrome protein: linking the replication checkpoint response to genome stability |journal=Aging |volume=3 |issue=3 |pages=311–8 |year=2011 |pmid=21389352 |pmc=3091524 |doi=10.18632/aging.100293 }}</ref>  WRN također može biti važan u održavanju i repliciranju [[telomera]], posebno replikaciji G-bogatih sekvenci.<ref name=Ding>{{cite journal |vauthors=Ding SL, Shen CY | title = Model of human aging: recent findings on Werner's and Hutchinson–Gilford progeria syndromes | journal = Clin Interv Aging | volume = 3 | issue = 3 | pages = 431–44 | year = 2008 | pmid = 18982914 | pmc = 2682376 | doi = 10.2147/CIA.S1957 }}</ref>

WRN je [[oligomer]] koji može djelovati kao monomer pri odmotavanju [[DNK]], ali kao dimer u [[rastvor]]u ili tetramer kada je kompleksiran s DNK, a primijećen je i u tetramernim i heksamernim oblicima. Difuzija WRN-a izmjerena je na 1,62<math> \tfrac{\mathrm{\mu m}^2}{\mathrm{s}} </math> u [[nukleoplazma|nukleoplazmi]] i 0,12  <math> \textstyle \tfrac{\mathrm{\mu m}^2}{\mathrm{s}} </math> u [[jedarce|jedarcadima]].<ref name="Bendtsen_2014">{{cite journal | author = Kristian Moss Bendtsen, Martin Borch Jensen, Alfred May, Lene JuelRasmussen, Ala Trusina, Vilhelm A. Bohr & Mogens H. Jensen | title = Dynamics of the DNA repair proteins WRN and BLM in the nucleoplasm and nucleoli | journal = European Biophysics Journal | year = 2014 | pmid = 25119658 | doi = 10.1007/s00249-014-0981-x | volume=43 | issue = 10–11 | pages=509–16| pmc = 5576897 }}</ref> [[Ortolozi]] WRN pronađeni su u brojnim drugim [[organizmi]]ma, uključujući [[Drosophila melanogaster|''Drosophila'']], ''[[Xenopus]]'' i [[Caenorhabditis elegans|''C. elegans'']]. WRN je važan za stabilnost [[genom]]a, a ćelije s mutacijama na WRN su podložnije oštećenju i prekidima DNK.<ref name="Rossi_2010">{{cite journal |vauthors=Rossi ML, Ghosh AK, Bohr VA | title = Roles of Werner syndrome protein in protection of genome integrity | journal = DNA Repair (Amst.) | volume = 9 | issue = 3 | pages = 331–44 | year = 2010 | pmid = 20075015 | pmc = 2827637 | doi = 10.1016/j.dnarep.2009.12.011 }}</ref>

[[N-kraj|Amino-terminal]] WRN-a uključen je i u aktivnosti [[helikaza]] i [[nukleaza]], dok [[C-kraj|karboksil-terminal]] stupa u interakciju s [[p53]] , važnim supresorom tumora.<ref name=Oshima_2000 /> WRN može funkcionirati kao egzonukleaza u popravci DNK, rekombinaciji ili replikaciji, kao i razlučivanju sekundarnih struktura DNK. Uključen je u migraciju grana u [[Hollidayev spoj|Hollidayevim spajanjim]]  i u interakciji je s drugim intermedijarima [[replikacija DNK|replikacije DNK]].<ref name = "pmid21389352"/> mRNA koja je kodirana za WRN identificirana je u većini ljudskih tkiva.<ref name="Oshima_2000">{{cite journal | author = Oshima J | title = The Werner syndrome protein: an update | journal = BioEssays | volume = 22 | issue = 10 | pages = 894–901 | year = 2000 | pmid = 10984715 | doi = 10.1002/1521-1878(200010)22:10<894::AID-BIES4>3.0.CO;2-B }}</ref>

=== [[Posttranslacijska modifikacija]] ===

[[Fosforilacija]] WRN-a u [[serin]]u/[[treonin]]u inhibira aktivnosti helikaze i egzonukleaze koje su važne za [[popravak DNK]] nakon replikacije. Defosforilacija na ovim mjestima pojačava katalitsku aktivnost WRN-a. Fosforilacija može uticati na druge [[posttranslacijske modifikacije]], uključujući [[sumoilacija|sumoilaciju]] i [[acetilacija|acetilaciju]].<ref name="Ding"/>

[[Metilacija]] WRN dovodi do isključivanja gena. Time se potiskuje proizvodnja proteina WRN i njegove funkcije u popravljanju DNK.<ref name="WRN nih ref">{{cite web|title=WRN|url=http://ghr.nlm.nih.gov/gene/WRN|publisher=US National Library of Medicine|access-date=18. 3. 2014}}</ref>

== Klinički značaj ==
[[Wernerov sindrom]] uzrokovan je [[mutacija|mutacijom]] s u genu WRN.<ref name=Oshima_2000 /> Poznato je da Wernerov sindrom uzrokuje više od 20 mutacija u WRN genu. Mnoge od ovih mutacija rezultiraju abnormalno skraćenim Wernerovim proteinom. Dokazi pokazuju da se promijenjeni [[protein]] ne transportira u [[ćelijsko jedro]], gdje normalno stupa u interakciju s DNK.<ref name="Huang">{{cite journal |vauthors=Huang S, Lee L, Hanson NB, Lenaerts C, Hoehn H, Poot M, Rubin CD, Chen DF, Yang CC, Juch H, Dorn T, Spiegel R, Oral EA, Abid M, Battisti C, Lucci-Cordisco E, Neri G, Steed EH, Kidd A, Isley W, Showalter D, Vittone JL, Konstantinow A, Ring J, Meyer P, Wenger SL, von Herbay A, Wollina U, Schuelke M, Huizenga CR, Leistritz DF, Martin GM, Mian IS, Oshima J | title = The spectrum of WRN mutations in Werner syndrome patients | journal = Hum. Mutat. | volume = 27 | issue = 6 | pages = 558–67 | year = 2006 | pmid = 16673358 | pmc = 1868417 | doi = 10.1002/humu.20337 }}</ref> Ovaj skraćeni protein se također može prebrzo razgraditi, što dovodi do gubitka Wernerovog proteina u ćeliji. Bez normalnog Werner0vog proteina u jedru, ćelije ne mogu obavljati akrivnosti replikacije, popravke i transkripcije DNK.<ref name="Lebel">{{cite journal | author = Lebel M | title = Werner syndrome: genetic and molecular basis of a premature aging disorder | journal = Cell. Mol. Life Sci. | volume = 58 | issue = 7 | pages = 857–67 | year = 2001 | pmid = 11497235 | doi = 10.1007/s00018-001-8398-y | s2cid = 24801894 }}</ref> Istraživači još uvijek utvrđuju kako ove mutacije uzrokuju pojavu preranog [[starenje|starenja]] viđenog kod Wernerovog sindroma.

== Uloge WRN -a u putevima popravljanja DNK ==

=== Popravak homolognom rekombinacijom ===
WRN je aktivan u [[homologna rekombinacija|homolognim rekombinacijama]]. Ćelije oštećene u genu '' WRN '' imaju 23-struko smanjenje spontane mitotske rekombinacije, sa posebnim nedostatkom u događajima tipa konverzije.<ref name="pmid11316787">{{cite journal |vauthors=Prince PR, Emond MJ, Monnat RJ |title=Loss of Werner syndrome protein function promotes aberrant mitotic recombination |journal=Genes Dev. |volume=15 |issue=8 |pages=933–8 |year=2001 |pmid=11316787 |pmc=312674 |doi=10.1101/gad.877001 }}</ref> Ćelije sa neispravnim   '' WRN'' izložene rendgenskim zracima, imaju više [[hromosom]]skih lomova i [[mikronukleus]]a od ćelija s [[divlji tip|divljim tipom]] WRN.<ref name="pmid7507567">{{cite journal |vauthors=Weirich-Schwaiger H, Weirich HG, Gruber B, Schweiger M, Hirsch-Kauffmann M |title=Correlation between senescence and DNA repair in cells from young and old individuals and in premature aging syndromes |journal=Mutat. Res. |volume=316 |issue=1 |pages=37–48 |year=1994 |pmid=7507567 |doi= 10.1016/0921-8734(94)90006-x}}</ref>  Ćelije sa  oštećenim u genom ''WRN'' nisu osjetljivije od ćelija divljeg tipa na [[gama zračenje]], [[UV-zrake]], 4-6 ciklobutanske [[pirimidin]]e ili mitomicin C, ali su osjetljive na inhibitore topoizomeraze tipa I i tipa II.<ref name="pmid9789047">{{cite journal |vauthors=Lebel M, Leder P |title=A deletion within the murine Werner syndrome helicase induces sensitivity to inhibitors of topoisomerase and loss of cellular proliferative capacity |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=95 |issue=22 |pages=13097–102 |year=1998 |pmid=9789047 |pmc=23722 |doi= 10.1073/pnas.95.22.13097}}</ref>   Ovi nalazi sugeriraju da protein WRN sudjeluje u homolognoj rekombinacijskoj popravci i u obradi zaustavljenih replikacijskih viljuški.<ref name="pmid11380620">{{cite journal |vauthors=Sakamoto S, Nishikawa K, Heo SJ, Goto M, Furuichi Y, Shimamoto A |title=Werner helicase relocates into nuclear foci in response to DNA damaging agents and co-localizes with RPA and Rad51 |journal=Genes Cells |volume=6 |issue=5 |pages=421–30 |year=2001 |pmid=11380620 |doi= 10.1046/j.1365-2443.2001.00433.x|s2cid=26078155 }}</ref>

=== Nehomologno spajanje krajeva ===
WRN ima važnu ulogu u [[nehomologno spsjanje krajeva|nehomolognom spajanju krajeva]] (NHEJ) pri [[popravak DNK|popravci DNK]]. Kao što pokazuju Shamanna et al.,<ref name="pmid27922005"/> WRN je regrutovan za dvolančane prekide (DSB) i učestvuje u NHEJ sa svojim enzimskim i neenzimskim funkcijama. U DSB-ima, u suradnji s [[Ku (protein)|Ku-om]], podstiče standardni ili kanonski NHEJ (c-NHEJ), popravljajući dvolančane lomove u DNK, svojim enzimskim funkcijama i sa priličnim stepenom tačnosti. WRN inhibira alternativni oblik NHEJ-a, nazvan alt-NHEJ ili [[spajanje krajeva posredovano mikrohomologijom]] (MMEJ). MMEJ je neprecizan način popravka za dvolančane prekide.

=== Popravka ekcizijom baza===
WRN ima ulogu u [[popravak ekscizijom baza|popravku ekscizijom baza]] (BER) DNK. Kao što pokazuju Das et al.,<ref name="pmid17611195"/> WRN se povezuje sa NEIL1 u ranom koraku otkrivanja oštećenja BER-a. WRN stimulira NEIL1 u uklanjanju oksidativnih [[lezija]]. [[NEIL1]] je [[DNK- glikozilaza]] koja inicira prvi korak u BER-u, cijepanjem baza oštećenih [[ROS|reaktivnim vrstama kisika]] (ROS) i uvođenjem preloma DNK lanca putem povezane aktivnosti NEIL1 s [[ligaza|ligazom]].<ref name="pmid24349107">{{cite journal |vauthors=Jacobs AC, Calkins MJ, Jadhav A, Dorjsuren D, Maloney D, Simeonov A, Jaruga P, Dizdaroglu M, McCullough AK, Lloyd RS |title=Inhibition of DNA glycosylases via small molecule purine analogs |journal=PLOS ONE |volume=8 |issue=12 |pages=e81667 |year=2013 |pmid=24349107 |pmc=3857224 |doi=10.1371/journal.pone.0081667 }}</ref>  [[NEIL1]] prepoznaje (ciljeve) i uklanja određene [[Reaktivne vrste kisika|ROS-om]]-oštećene baze, a zatim ekscidira [[AP-mjesto|abasicno mjesto]] putem eliminacije β, δ, ostavljajući 3 ′ i 5 ′ fosfatni završetak. NEIL1 prepoznaje oksidirane [[pirimidin]]e, formamidopirimidine, [[timin]]ske ostatke oksidirane na metilnoj skupini i oba stereoizomera [[timin-glikol]]a.<ref name="pmid20955798">{{cite journal | vauthors = Nemec AA, Wallace SS, Sweasy JB | title = Variant base excision repair proteins: contributors to genomic instability | journal = Seminars in Cancer Biology | volume = 20 | issue = 5 | pages = 320–8 | date = Oct 2010 | pmid = 20955798 | pmc = 3254599 | doi = 10.1016/j.semcancer.2010.10.010 }}</ref>

WRN također učestvuje u BER-u, interakcijom sa [[DNK-polimeraza lambda|Polλ]].<ref name="pmid22753033"/>  WRN se veže za katalitski domen Polλ i specifično stimulira popunjavanje DNK praznina Polλom, preko [[8-okso-2'-deoksiguanozin|8-okso-G]], nakon čega slijedi sinteza istiskivanjem niti. Ovo omogućava WRN-u da promovira sintezu popravke DNK sa dugim zakrpama pomoću Polλ, tokom [[MUTYH]]-inicirane popravke 8-okso-G: A u parovima.

=== Oporavak pri zaustavljanju replikacije ===
WRN je također uključen u oporavak pri zaustavljanju replikacije. Ako je WRN neispravan, zaustavljanje replikacije dovodi do nakupljanja DSB -a i pojačane fragmentacije hromosoma.<ref name=Pichierri>{{cite journal |vauthors=Pichierri P, Nicolai S, Cignolo L, Bignami M, Franchitto A |title=The RAD9-RAD1-HUS1 (9.1.1) complex interacts with WRN and is crucial to regulate its response to replication fork stalling |journal=Oncogene |volume=31 |issue=23 |pages=2809–23 |year=2012 |pmid=22002307 |pmc=3272477 |doi=10.1038/onc.2011.468 }}</ref> Kao što su pokazali Pichierri et al.,<ref name =Pichierri /> WRN stupa u interakciju sa kompleksom [[RAD9A|RAD9]]-[[homolog RAD1|RAD1]]-[[HUS1]] (9.1.1), jednim od centralnih faktora kontrolne tačke replikacije. Ova interakcija je posredovana vezivanjem podjedinice RAD1 za [[N-terminal]]nu regiju WRN-a i instrument je za relokalizaciju WRN-a u jedarna žarišta i njenu fosforilaciju kao odgovor na zaustavljanje replikacije. (U nedostatku oštećenja DNK ili zaustavljanja replikacijske viljuške, protein WRN ostaje lokaliziran u [[jedarce|jedarcadima]].<ref name="pmid11256630">{{cite journal |vauthors=Constantinou A, Tarsounas M, Karow JK, Brosh RM, Bohr VA, Hickson ID, West SC |title=Werner's syndrome protein (WRN) migrates Holliday junctions and co-localizes with RPA upon replication arrest |journal=EMBO Rep. |volume=1 |issue=1 |pages=80–4 |year=2000 |pmid=11256630 |pmc=1083680 |doi= 10.1093/embo-reports/kvd004}}</ref>)  Interakcija WRN -a sa kompleksom 9.1.1 rezultira sprječavanjem stvaranja DSB -a na zaustavljenim replikacijskim račvama.<ref name = Pichierri/>

== Nedostatak ''WRN'' u kancerima ==

Ćelije koje eksprimiraju ograničene količine WRN imaju povišene frekvencije [[mutacija]] u poređenju sa ćelijama [[divlji tip|divljeg tipa]].<ref name="pmid22351772">{{cite journal |vauthors=Kamath-Loeb AS, Shen JC, Schmitt MW, Loeb LA |title=The Werner syndrome exonuclease facilitates DNA degradation and high fidelity DNA polymerization by human DNA polymerase δ |journal=J. Biol. Chem. |volume=287 |issue=15 |pages=12480–90 |year=2012 |pmid=22351772 |pmc=3320997 |doi=10.1074/jbc.M111.332577 }}</ref>  Povećana mutacija može uzrokovati rak. Pacijenti s Wernerovim sindromom, s [[homozigot]]nim mutacijama u genu '' WRN '', imaju povećanu učestalost karcinoma, uključujući sarkome mehkih tkiva, osteosarkom, [[rak štitnjače]] i [[melanom]].<ref name="pmid8722214">{{cite journal |vauthors=Goto M, Miller RW, Ishikawa Y, Sugano H |title=Excess of rare cancers in Werner syndrome (adult progeria) |journal=Cancer Epidemiol. Biomarkers Prev. |volume=5 |issue=4 |pages=239–46 |year=1996 |pmid=8722214 }}</ref>

Mutacije u '' WRN '' su rijetke u općoj populaciji. Stopa gubitka [[heterozigot]]e mutacijske funkcije u ''WRN'' je otprilike jedan na milion. U [[japan]]skoj populaciji stopa je 6/1.000, što je više, ali još uvijek rijetko.<ref name="pmid21365542">{{cite journal |vauthors=Chun SG, Shaeffer DS, Bryant-Greenwood PK |title=The Werner's Syndrome RecQ helicase/exonuclease at the nexus of cancer and aging |journal=Hawaii Med J |volume=70 |issue=3 |pages=52–5 |year=2011 |pmid=21365542 |pmc=3071901 }}</ref>

Mutacijski nedostaci u genu ''WRN'' relativno su rijetki u ćelijama raka u usporedbi sa učestalošću [[epigenetika|epigenetičkih]] promjena u ''WRN'', koje smanjuju njegovu ekspresiju i mogu pridonijeti karcinogenezi. Situacija je slična s drugim genima za [[popravak DNK]], čija je ekspresija smanjena kod karcinoma zbog uglavnom epigenetičkih promjena, a ne mutacija.

Tabela prikazuje rezultate analize 630 ljudskih primarnih tumora za ''WRN''-ovu CpG-otočnu hipermetilaciju.<ref name=Agrelo>{{cite journal |vauthors=Agrelo R, Cheng WH, Setien F, Ropero S, Espada J, Fraga MF, Herranz M, Paz MF, Sanchez-Cespedes M, Artiga MJ, Guerrero D, Castells A, von Kobbe C, Bohr VA, Esteller M |title=Epigenetic inactivation of the premature aging Werner syndrome gene in human cancer |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=103 |issue=23 |pages=8822–7 |year=2006 |pmid=16723399 |pmc=1466544 |doi=10.1073/pnas.0600645103 }}</ref>  Ova [[metilacija|hipermetilacija]] uzrokovala je smanjenu ekspresiju proteina WRN-a, uobičajenog događaja u tumorigenezi.<ref name=Agrelo/>

{| class="wikitable sortable"
|+ Učestalost metilacije promotora '' WRN '' kod sporadičnih karcinoma<br>
! [[Kancer]] !!Frekvencija redukcije u kancerima<ref name=Agrelo />
|-
![[Rak debelog crijeva]]|| 37,9%
|-
![[Nemaloćelijski rak pluća]]|| 37,5%
|-
![[Rak želuca]]|| 25%
|-
![[Rak prostate]]|| 20%
|-
![[Rak dojke]]|| 17,2%
|-
![[Rak štitnjače]]|| 12,5%
|-
!Ne[[Hodgkinov limfom]]|| 23,7%
|-
![[Akutna mijeloblastna leukemija]]|| 4,8%
|-
![[Hondrosarkom]]|| 33,3%
|-
![[Osteosarkom]]|| 11,1%
|}

== Interakcije ==
Helikaza ovisna o ATP-u Wernerov sindroma  [[interakcija protein-protein|stupa u interakcije]] s:
{{refbegin|3}}
* [[Prorein Bloomovog sindroma|BLM]]<ref name = pmid11919194>{{cite journal | date = juni 2002 |vauthors=von Kobbe C, Karmakar P, Dawut L, Opresko P, Zeng X, Brosh RM, Hickson ID, Bohr VA | title = Colocalization, physical, and functional interaction between Werner and Bloom syndrome proteins | journal = J. Biol. Chem. | volume = 277 | issue = 24 | pages = 22035–44 | pmid = 11919194 | doi = 10.1074/jbc.M200914200| doi-access = free }}</ref> 
* [[DNK-PKc]],<ref name = pmid10608806>{{cite journal | date = Dec 1999 |vauthors=Kim ST, Lim DS, Canman CE, Kastan MB | title = Substrate specificities and identification of putative substrates of ATM kinase family members | journal = J. Biol. Chem. | volume = 274 | issue = 53 | pages = 37538–43 | pmid = 10608806 | doi = 10.1074/jbc.274.53.37538| doi-access = free }}</ref><ref name = pmid11889123>{{cite journal | date = maj 2002 |vauthors=Karmakar P, Piotrowski J, Brosh RM, Sommers JA, Miller SP, Cheng WH, Snowden CM, Ramsden DA, Bohr VA | title = Werner protein is a target of DNA-dependent protein kinase in vivo and in vitro, and its catalytic activities are regulated by phosphorylation | journal = J. Biol. Chem. | volume = 277 | issue = 21 | pages = 18291–302 | pmid = 11889123 | doi = 10.1074/jbc.M111523200| doi-access = free }}</ref> 
* [[FEN1]],<ref name = pmid14688284>{{cite journal | date = mart 2004 |vauthors=Sharma S, Sommers JA, Wu L, Bohr VA, Hickson ID, Brosh RM | title = Stimulation of flap endonuclease-1 by the Bloom's syndrome protein | journal = J. Biol. Chem. | volume = 279 | issue = 11 | pages = 9847–56 | pmid = 14688284 | doi = 10.1074/jbc.M309898200| doi-access = free }}</ref><ref name = pmid11598021>{{cite journal | date = oktobar 2001 |vauthors=Brosh RM, von Kobbe C, Sommers JA, Karmakar P, Opresko PL, Piotrowski J, Dianova I, Dianov GL, Bohr VA | title = Werner syndrome protein interacts with human flap endonuclease 1 and stimulates its cleavage activity | journal = EMBO J. | volume = 20 | issue = 20 | pages = 5791–801 | pmid = 11598021 | pmc = 125684 | doi = 10.1093/emboj/20.20.5791}}</ref> 
* [[Ku70]],<ref name = pmid12177300>{{cite journal | date = august 2002 |vauthors=Karmakar P, Snowden CM, Ramsden DA, Bohr VA | title = Ku heterodimer binds to both ends of the Werner protein and functional interaction occurs at the Werner N-terminus | journal = Nucleic Acids Res. | volume = 30 | issue = 16 | pages = 3583–91 | pmid = 12177300 | pmc = 134248 | doi = 10.1093/nar/gkf482}}</ref><ref name = pmid10880505>{{cite journal | date = septembar 2000 |vauthors=Li B, Comai L | title = Functional interaction between Ku and the werner syndrome protein in DNA end processing | journal = J. Biol. Chem. | volume = 275 | issue = 37 | pages = 28349–52 | pmid = 10880505 | doi = 10.1074/jbc.C000289200| doi-access = free }}</ref> 
* [[Ku80]],<ref name = pmid12177300/><ref name = pmid10880505/> 
* [[P53]],<ref name = pmid12080066>{{cite journal | date = august 2002 |vauthors=Yang Q, Zhang R, Wang XW, Spillare EA, Linke SP, Subramanian D, Griffith JD, Li JL, Hickson ID, Shen JC, Loeb LA, Mazur SJ, Appella E, Brosh RM, Karmakar P, Bohr VA, Harris CC | title = The processing of Holliday junctions by BLM and WRN helicases is regulated by p53 | journal = J. Biol. Chem. | volume = 277 | issue = 35 | pages = 31980–7 | pmid = 12080066 | doi = 10.1074/jbc.M204111200| doi-access = free }}</ref><ref name = pmid11427532>{{cite journal | date = septembar 2001 |vauthors=Brosh RM, Karmakar P, Sommers JA, Yang Q, Wang XW, Spillare EA, Harris CC, Bohr VA | title = p53 Modulates the exonuclease activity of Werner syndrome protein | journal = J. Biol. Chem. | volume = 276 | issue = 37 | pages = 35093–102 | pmid = 11427532 | doi = 10.1074/jbc.M103332200| doi-access = free }}</ref> 
* [[PCNA]],<ref name = pmid12633936>{{cite journal | date = februar 2003 |vauthors=Rodríguez-López AM, Jackson DA, Nehlin JO, Iborra F, Warren AV, Cox LS | title = Characterisation of the interaction between WRN, the helicase/exonuclease defective in progeroid Werner's syndrome, and an essential replication factor, PCNA | journal = Mech. Ageing Dev. | volume = 124 | issue = 2 | pages = 167–74 | pmid = 12633936 | doi = 10.1016/S0047-6374(02)00131-8|s2cid=37287691 }}</ref><ref name = pmid10871373>{{cite journal | date = juni 2000 |vauthors=Huang S, Beresten S, Li B, Oshima J, Ellis NA, Campisi J | title = Characterization of the human and mouse WRN 3'-->5' exonuclease | journal = Nucleic Acids Res. | volume = 28 | issue = 12 | pages = 2396–405 | pmid = 10871373 | pmc = 102739 | doi = 10.1093/nar/28.12.2396}}</ref> 
* [[TERF2]],<ref name = pmid12181313>{{cite journal | date = oktobar 2002 |vauthors=Opresko PL, von Kobbe C, Laine JP, Harrigan J, Hickson ID, Bohr VA | title = Telomere-binding protein TRF2 binds to and stimulates the Werner and Bloom syndrome helicases | journal = J. Biol. Chem. | volume = 277 | issue = 43 | pages = 41110–9 | pmid = 12181313 | doi = 10.1074/jbc.M205396200| doi-access = free }}</ref> i
* [[WRNIP1]].<ref name = pmid11301316>{{cite journal | date = juni 2001 |vauthors=Branzei D, Hayashi T, Suzuki H, Masuko T, Onoda F, Heo SJ, Ikeda H, Shimamoto A, Furuichi Y, Seki M, Enomoto T | title = A novel protein interacts with the Werner's syndrome gene product physically and functionally | journal = J. Biol. Chem. | volume = 276 | issue = 23 | pages = 20364–9 | pmid = 11301316 | doi = 10.1074/jbc.C100035200| doi-access = free }}</ref> 
{{refend}}
{{Clear}}

== Reference ==
{{Reflist|35em}}

== Dopunska literatura==
{{Refbegin|35em}}
* {{cite journal |vauthors=Comai L, Li B | title=The Werner syndrome protein at the crossroads of DNA repair and apoptosis | journal=Mech Ageing Dev | year=2004 | pages=521–8 | volume=125 | issue=8  | pmid=15336909 | doi=10.1016/j.mad.2004.06.004| s2cid=30529954 | url=https://zenodo.org/record/894614 }}
* {{cite journal |vauthors=Lee JW, Harrigan J, Opresko PL, Bohr VA | title=Pathways and functions of the Werner syndrome protein | journal=Mech Ageing Dev | year=2005 | pages=79–86 | volume=126 | issue=1  | pmid=15610765 | doi=10.1016/j.mad.2004.09.011| s2cid=39834357 }}
* {{cite journal |author1=Monnat RJ Jr |author2=Saintigny Y | title=Werner syndrome protein--unwinding function to explain disease | journal=Sci Aging Knowledge Environ | year=2004 | pages=re3 | volume=2004 | issue=13  | pmid=15056797 | doi=10.1126/sageke.2004.13.re3|url=https://hal-cea.archives-ouvertes.fr/cea-01938173/file/Sageke_Werner.pdf }}
* {{cite journal |vauthors=Ozgenc A, Loeb LA | title=Current advances in unraveling the function of the Werner syndrome protein | journal=Mutat Res | year=2005 | pages=237–51 | volume=577 | issue=1–2  | pmid=15946710 | doi=10.1016/j.mrfmmm.2005.03.020}}
* {{cite journal |vauthors=Swanson C, Saintigny Y, Emond MJ, Monnat RJ Jr | title=The Werner syndrome protein has separable recombination and survival functions | journal=DNA Repair (Amst) | year=2004 | pages=475–82 | volume=3 | issue=5  | pmid=15084309 | doi=10.1016/j.dnarep.2004.01.002| url=http://monnatlab.gs.washington.edu/pdf/2004_Swanson.pdf }}
*{{cite journal  |vauthors=Moser MJ, Oshima J, Monnat RJ |title=WRN mutations in Werner syndrome |journal=Hum. Mutat. |volume=13 |issue= 4 |pages= 271–9 |year= 1999 |pmid= 10220139 |doi=10.1002/(SICI)1098-1004(1999)13:4<271::AID-HUMU2>3.0.CO;2-Q}}
*{{cite journal  |vauthors=Kastan MB, Lim DS |title=The many substrates and functions of ATM |journal=Nat. Rev. Mol. Cell Biol. |volume=1 |issue= 3 |pages= 179–86 |year= 2001 |pmid= 11252893 |doi= 10.1038/35043058 |s2cid=10691352 }}
{{Refend}}

== Vanjski linkovi ==
* {{cite book |vauthors=Oshima J, Martin GM, Hisama FM |title=Werner Syndrome |url=https://www.ncbi.nlm.nih.gov/books/NBK1514/ |date=februar 2012 |id=NBK1514 |pmid=20301687}} In {{cite book |veditors=Pagon RA, Bird TD, Dolan CR |title=GeneReviews [Internet] |year=1993 |publisher=University of Washington, Seattle |location=Seattle WA |url=https://www.ncbi.nlm.nih.gov/books/n/gene/TOC/ |display-editors=etal}}
* [https://www.genecards.org/cgi-bin/carddisp?WRN GeneCard]
* [http://www.wernersyndrome.org/ws_wrn.html Werner Syndrome Mutational Database] {{Webarchive|url=https://web.archive.org/web/20120721213533/http://www.wernersyndrome.org/ws_wrn.html |date=21. 7. 2012 }}

{{PDB Gallery|geneid=7486}}
{{popravak DNK}}
{{enzimi}}

{{DEFAULTSORT:Werner Syndrome Atp-Dependent Helicase}}
[[Kategorija:Geni na hromosomu 8]]
[[Kategorija:Enzimi]]
[[Kategorija:Ljudski proteini]]
[[Kategorija:Proteomika]]