View source for Werner syndrome helicase

{{Infobox_gene}}
"'''Werner syndrome ATP-dependent helicase'''" also known as '''DNA helicase, RecQ-like type 3''' is an [[enzyme]] that in humans is encoded by the WRN [[gene]]. WRN is a member of the [[RecQ helicase|RecQ Helicase]] family.<ref name=Monnat />  Helicase enzymes generally unwind and separate double-stranded [[DNA]]. These activities are necessary before DNA can be copied in preparation for cell division ([[DNA replication]]). Helicase enzymes are also critical for making a blueprint of a gene for protein production, a process called [[Transcription (genetics)|transcription]]. Further evidence suggests that Werner protein plays a critical role in [[DNA repair|repairing DNA]]. Overall, this protein helps maintain the structure and integrity of a person's DNA.

The WRN gene is located on the short (p) arm of [[chromosome 8 (human)|chromosome 8]] between positions 12 and 11.2, from [[base pair]] 31,010,319 to base pair 31,150,818.

== Structure and function ==

WRN is a member of the [[RecQ helicase|RecQ Helicase]] family. It is the only RecQ Helicase that contains 3' to 5' [[exonuclease]] activity. These exonuclease activities include degradation of recessed 3' ends and initiation of DNA degradation from a gap in dsDNA. WRN is important in [[DNA repair|repair]] of double strand breaks by [[homologous recombination]]<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|url=}}</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 |url=}}</ref> or [[non-homologous end joining]],<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 |issue= |pages=13785 |year=2016 |pmid=27922005 |pmc=5150655 |doi=10.1038/ncomms13785 |url=}}</ref> repair of single nucleotide damages by [[base excision repair]],<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 |url=}}</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 |url=}}</ref><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=October 2010  | pmid = 20934517 | pmc = 3040982 | doi = 10.1016/j.semcancer.2010.10.002 }}</ref> and is effective in replication arrest recovery.<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 |url=}}</ref>  WRN may also be important in telomere maintenance and replication, especially the replication of the G-rich sequences.<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 is an [[oligomer]] that can act as a monomer when unwinding DNA, but as a dimer in solution or a tetramer when complexed with DNA, and has also been observed in tetrameric and hexameric forms. The diffusion of WRN has been measured to 1.62   <math> \tfrac{\mathrm{\mu m}^2}{\mathrm{s}} </math> in nucleoplasm and 0.12  <math> \textstyle \tfrac{\mathrm{\mu m}^2}{\mathrm{s}} </math>  at nucleoli.<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 | pages=509–16}}</ref> Orthologs of WRN have been found in a number of other organisms, including [[Drosophila melanogaster|''Drosohphila'']], ''[[Xenopus]]'', and [[Caenorhabditis elegans|''C. elegans'']]. WRN is important to genome stability, and cells with mutations to WRN are more susceptible to DNA damage and DNA breaks.<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>

The [[N-terminus|amino terminus]] of WRN is involved in both [[helicase]] and [[nuclease]] activities, while the [[C-terminus|carboxyl-terminus]] interacts with [[p53]], an important tumor suppressor.<ref name=Oshima_2000 /> WRN may function as an exonuclease in DNA repair, recombination, or replication, as well as resolution of DNA secondary structures. It is involved in branch migration at [[Holliday junction]]s, and it interacts with other DNA replication intermediates.<ref name="pmid21389352"/> mRNA that codes for WRN has been identified in most human tissues.<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>

=== Post-translational modification ===

Phosphorylation of WRN at serine/threonine inhibits helicase and exonuclease activities which are important to post-replication DNA repair. De-phosphorylation at these sites enhances the catalytic activities of WRN. Phosphorylation may affect other post-translational modifications, including sumoylation and acetylation.<ref name="Ding"/>

Methylation of WRN causes the gene to turn off. This suppresses the production of the WRN protein and its functions in DNA repair.<ref name="WRN nih ref">{{cite web|title=WRN|url=http://ghr.nlm.nih.gov/gene/WRN|publisher=US National Library of Medicine|accessdate=18 March 2014}}</ref>

== Clinical significance ==
[[Werner syndrome]] is caused by [[mutation]]s in the WRN gene.<ref name=Oshima_2000 />  More than 20 mutations in the WRN gene are known to cause Werner syndrome. Many of these mutations result in an abnormally shortened Werner protein. Evidence suggests that the altered [[protein]] is not transported into the [[cell nucleus]], where it normally interacts with DNA.<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> This shortened protein may also be broken down too quickly, leading to a loss of Werner protein in the cell. Without normal Werner protein in the nucleus, cells cannot perform the tasks of DNA replication, repair, and transcription.<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 }}</ref> Researchers are still determining how these mutations cause the appearance of premature [[aging]] seen in Werner syndrome.

==WRN roles in DNA repair pathways==

===Homologous recombinational repair===
WRN is active in [[homologous recombination]].  Cells defective in the ''WRN'' gene have a 23-fold reduction in spontaneous mitotic recombination, with especial deficiency in conversion-type events.<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 |url=}}</ref>  ''WRN'' defective cells, when exposed to x-rays, have more chromosome breaks and micronuclei than cells with wild-type 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|url=}}</ref>   Cells defective in the ''WRN'' gene are not more sensitive than wild-type cells to gamma-irradiation, UV light, 4 – 6 cyclobutane pyrimidines, or mitomycin C, but are sensitive to type I and type II topoisomerase inhibitors.<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|url=}}</ref>   These findings suggested that the WRN protein takes part in homologous recombinational repair and in the processing of stalled replication forks.<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|url=}}</ref>

===Non-homologous end joining===
WRN has an important role in [[non-homologous end joining]] (NHEJ) DNA repair.  As shown by Shamanna et al.,<ref name="pmid27922005"/> WRN is recruited to double-strand breaks (DSBs) and participates in NHEJ with its enzymatic and non-enzymatic functions. At DSBs, in association with [[Ku (protein)]], it promotes standard or canonical NHEJ (c-NHEJ), repairing double-strand breaks in DNA with its enzymatic functions and with a fair degree of accuracy.  WRN inhibits an alternative form of NHEJ, called alt-NHEJ or [[microhomology-mediated end joining]] (MMEJ).  MMEJ is an inaccurate mode of repair for double-strand breaks.

===Base excision repair===
WRN has a role in [[base excision repair]] (BER) of DNA.  As shown by Das et al.,<ref name="pmid17611195"/> WRN associates with NEIL1 in the early damage-sensing step of BER.  WRN stimulates NEIL1 in excision of oxidative lesions.  [[NEIL1]] is a [[DNA glycosylase]] that initiates the first step in BER by cleaving bases damaged by [[reactive oxygen species]] (ROS) and introducing a DNA strand break via NEIL1's associated lyase activity.<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 |url=}}</ref>  [[NEIL1]] recognizes (targets) and removes certain [[Reactive oxygen species|ROS]]-damaged bases and then incises the [[AP site|abasic site]] via β,δ elimination, leaving 3′ and 5′ phosphate ends. NEIL1 recognizes oxidized [[pyrimidine]]s, formamidopyrimidines, [[thymine]] residues oxidized at the methyl group, and both stereoisomers of [[thymine glycol]].<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 also participates in BER through its interaction with [[DNA polymerase lambda|Polλ]].<ref name="pmid22753033"/>  WRN binds to the catalytic domain of Polλ and specifically stimulates DNA gap filling by Polλ over [[8-Oxo-2'-deoxyguanosine|8-oxo-G]] followed by strand displacement synthesis.  This allows WRN to promote long-patch DNA repair synthesis by Polλ during [[MUTYH]]-initiated repair of 8-oxo-G:A mispairs.

===Replication arrest recovery===
WRN is also involved in replication arrest recovery.  If WRN is defective, replication arrest results in accumulation of DSBs and enhanced chromosome fragmentation.<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 |url=}}</ref>  As shown by Pichierri et al.,<ref name=Pichierri /> WRN interacts with the [[RAD9A|RAD9]]-[[RAD1 homolog|RAD1]]-[[HUS1]] (9.1.1) complex, one of the central factors of the replication checkpoint. This interaction is mediated by the binding of the RAD1 subunit to the N-terminal region of WRN and is instrumental for WRN relocalization to nuclear foci and its phosphorylation in response to replication arrest.  (In the absence of DNA damage or replication fork stalling, WRN protein remains localized to the nucleoli.<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|url=}}</ref>)  The interaction of WRN with the 9.1.1 complex results in prevention of DSB formation at stalled replication forks.<ref name=Pichierri />

==''WRN'' deficiencies in cancer==

Cells expressing limiting amounts of WRN have elevated mutation frequencies compared with wildtype cells.<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 |url=}}</ref>  Increased mutation may give rise to cancer.  Patients with Werner Syndrome, with homozygous mutations in the ''WRN'' gene, have an increased incidence of cancers, including soft tissue sarcomas, osteosarcoma, thyroid cancer and melanoma.<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 |doi= |url=}}</ref>

Mutations in ''WRN'' are rare in the general population.  The rate of heterozygous loss of-function mutation in ''WRN'' is approximately one per million.  In a Japanese population the rate is 6 per 1,000, which is higher, but still infrequent.<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 |doi= |url=}}</ref>

Mutational defects in the ''WRN'' gene are relatively rare in cancer cells compared to the frequency of epigenetic alterations in ''WRN'' that reduce ''WRN'' expression and could contribute to carcinogenesis.  The situation is similar to other DNA repair genes whose expression is reduced in cancers due to mainly epigenetic alterations rather than mutations (see [[Cancer epigenetics#Frequencies of epimutations in DNA repair genes|Frequencies of epimutations in DNA repair genes]]).<ref>Carol Bernstein and Harris Bernstein (2015). Epigenetic Reduction of DNA Repair in Progression to Cancer, Advances in DNA Repair, Prof. Clark Chen (Ed.), {{ISBN|978-953-51-2209-8}}, InTech,  Available from: http://www.intechopen.com/books/advances-in-dna-repair/epigenetic-reduction-of-dna-repair-in-progression-to-cancer</ref>

The table shows results of analysis of 630 human primary tumors for ''WRN'' CpG island hypermethylation.<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 |url=}}</ref>  This hypermethylation caused reduced protein expression of WRN, a common event in tumorigenesis.<ref name=Agrelo />

{| class="wikitable sortable"
|+ Frequency of ''WRN'' promoter methylation in sporadic cancers
! Cancer !!Frequency of reduction in cancer<ref name=Agrelo />
|-
!Colorectal cancer|| 37.9%
|-
!Non-small cell lung cancer|| 37.5%
|-
!Gastric cancer|| 25%
|-
!Prostate cancer|| 20%
|-
!Breast cancer|| 17.2%
|-
!Thyroid cancer|| 12.5%
|-
!Non-Hodgkin lymphoma|| 23.7%
|-
!Acute myeloblastic leukemia|| 4.8%
|-
!Chondrosarcomas|| 33.3%
|-
!Osteosarcomas|| 11.1%
|}

== Interactions ==
Werner syndrome ATP-dependent helicase has been shown to [[Protein-protein interaction|interact]] with:
{{div col|colwidth=20em}}
* [[Bloom syndrome protein|BLM]]<ref name = pmid11919194>{{cite journal | date = June 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}}</ref> 
* [[DNA-PKcs]],<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}}</ref><ref name = pmid11889123>{{cite journal | date = May 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}}</ref> 
* [[Flap structure-specific endonuclease 1|FEN1]],<ref name = pmid14688284>{{cite journal | date = March 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}}</ref><ref name = pmid11598021>{{cite journal | date = October 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 = September 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}}</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}}</ref><ref name = pmid11427532>{{cite journal | date = September 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}}</ref> 
* [[PCNA]],<ref name = pmid12633936>{{cite journal | date = February 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}}</ref><ref name = pmid10871373>{{cite journal | date = June 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 = October 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}}</ref> and
* [[WRNIP1]].<ref name = pmid11301316>{{cite journal | date = June 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}}</ref> 
{{Div col end}}
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== References ==
{{Reflist|35em}}

== Further reading ==
{{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}}
* {{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}}
* {{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}}
* {{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}}
*{{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 }}
{{Refend}}

== External links ==
* {{cite book |vauthors=Oshima J, Martin GM, Hisama FM |title=Werner Syndrome |url=https://www.ncbi.nlm.nih.gov/books/NBK1514/ |date=February 2012 |id=NBK1514 |pmid=20301687}} In {{cite book |veditors=Pagon RA, Bird TD, Dolan CR |title=GeneReviews™ &#x05B;Internet&#x05D; |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]

{{PDB Gallery|geneid=7486}}
{{DNA repair}}

{{DEFAULTSORT:Werner Syndrome Atp-Dependent Helicase}}
[[Category:Genes on human chromosome 8]]