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Werner syndrome ATP-dependent helicase

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Title: Werner syndrome ATP-dependent helicase  
Author: World Heritage Encyclopedia
Language: English
Subject: Epigenetics, Bloom syndrome protein, Flap structure-specific endonuclease 1, Werner syndrome, ERCC1
Collection: Genes on Human Chromosome 8, Human Genes
Publisher: World Heritage Encyclopedia

Werner syndrome ATP-dependent helicase

Werner syndrome, RecQ helicase-like
Structure of DNA- and protein- binding motif of Werner protein. PDB rendering based on 2axl.
Available structures
PDB Ortholog search: PDBe, RCSB
Symbols  ; RECQ3; RECQL2; RECQL3
External IDs GeneCards:
EC number
RNA expression pattern
Species Human Mouse
RefSeq (mRNA)
RefSeq (protein)
Location (UCSC)
PubMed search

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 family.[1] 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. Further evidence suggests that Werner protein plays a critical role in 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 between positions 12 and 11.2, from base pair 31,010,319 to base pair 31,150,818.


  • Structure and function 1
    • Post-translational modification 1.1
  • Clinical significance 2
  • Interactions 3
  • References 4
  • Further reading 5
  • External links 6

Structure and function

WRN is a member of the 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 reparation of double stranded breaks, nonhomologous end joining, and base excision repair.[1] WRN may also be important in telomere maintenance and replication, especially the replication of the G-rich sequences.[2]

WRN is an Drosohphila, Xenopus, and C. elegans. WRN is important to genome stability, and cells with mutations to WRN are more susceptible to DNA damage and DNA breaks.[4]

The amino terminus of WRN is involved in both helicase and nuclease activities, while the carboxyl-terminus interacts with p53, an important tumor suppressor.[5] 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 junctions, and it interacts with other DNA replication intermediates.[6] mRNA that codes for WRN has been identified in most human tissues.[5]

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.[2]

Methylation of WRN causes the gene to turn off. This suppresses the production of the WRN protein and its functions in DNA repair.[7]

Clinical significance

Werner syndrome is caused by mutations in the WRN gene.[5] 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.[8] 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.[9] Researchers are still determining how these mutations cause the appearance of premature aging seen in Werner syndrome.


Werner syndrome ATP-dependent helicase has been shown to interact with:


  1. ^ a b Monnat RJ (October 2010). "Human RECQ helicases: roles in DNA metabolism, mutagenesis and cancer biology". Semin. Cancer Biol. 20 (5): 329–39.  
  2. ^ a b Ding SL, Shen CY (2008). "Model of human aging: recent findings on Werner's and Hutchinson-Gilford progeria syndromes". Clin Interv Aging 3 (3): 431–44.  
  3. ^ Kristian Moss Bendtsen, Martin Borch Jensen, Alfred May, Lene JuelRasmussen, Ala Trusina, Vilhelm A. Bohr & Mogens H. Jensen (2014). "Dynamics of the DNA repair proteins WRN and BLM in the nucleoplasm and nucleoli". European Biophysics Journal 43: 509–16.  
  4. ^ Rossi ML, Ghosh AK, Bohr VA (2010). "Roles of Werner syndrome protein in protection of genome integrity". DNA Repair (Amst.) 9 (3): 331–44.  
  5. ^ a b c Oshima J (2000). "The Werner syndrome protein: an update". BioEssays 22 (10): 894–901.  
  6. ^ Pichierri P, Ammazzalorso F, Bignami M, Franchitto A (2011). "The Werner syndrome protein: linking the replication checkpoint response to genome stability". Aging (Albany NY) 3 (3): 311–8.  
  7. ^ "WRN". US National Library of Medicine. Retrieved 18 March 2014. 
  8. ^ 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 (2006). "The spectrum of WRN mutations in Werner syndrome patients". Hum. Mutat. 27 (6): 558–67.  
  9. ^ Lebel M (2001). "Werner syndrome: genetic and molecular basis of a premature aging disorder". Cell. Mol. Life Sci. 58 (7): 857–67.  
  10. ^ von Kobbe C, Karmakar P, Dawut L, Opresko P, Zeng X, Brosh RM, Hickson ID, Bohr VA (June 2002). "Colocalization, physical, and functional interaction between Werner and Bloom syndrome proteins". J. Biol. Chem. 277 (24): 22035–44.  
  11. ^ Kim ST, Lim DS, Canman CE, Kastan MB (Dec 1999). "Substrate specificities and identification of putative substrates of ATM kinase family members". J. Biol. Chem. 274 (53): 37538–43.  
  12. ^ Karmakar P, Piotrowski J, Brosh RM, Sommers JA, Miller SP, Cheng WH, Snowden CM, Ramsden DA, Bohr VA (May 2002). "Werner protein is a target of DNA-dependent protein kinase in vivo and in vitro, and its catalytic activities are regulated by phosphorylation". J. Biol. Chem. 277 (21): 18291–302.  
  13. ^ Sharma S, Sommers JA, Wu L, Bohr VA, Hickson ID, Brosh RM (March 2004). "Stimulation of flap endonuclease-1 by the Bloom's syndrome protein". J. Biol. Chem. 279 (11): 9847–56.  
  14. ^ Brosh RM, von Kobbe C, Sommers JA, Karmakar P, Opresko PL, Piotrowski J, Dianova I, Dianov GL, Bohr VA (October 2001). "Werner syndrome protein interacts with human flap endonuclease 1 and stimulates its cleavage activity". EMBO J. 20 (20): 5791–801.  
  15. ^ a b Karmakar P, Snowden CM, Ramsden DA, Bohr VA (August 2002). "Ku heterodimer binds to both ends of the Werner protein and functional interaction occurs at the Werner N-terminus". Nucleic Acids Res. 30 (16): 3583–91.  
  16. ^ a b Li B, Comai L (September 2000). "Functional interaction between Ku and the werner syndrome protein in DNA end processing". J. Biol. Chem. 275 (37): 28349–52.  
  17. ^ 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 (August 2002). "The processing of Holliday junctions by BLM and WRN helicases is regulated by p53". J. Biol. Chem. 277 (35): 31980–7.  
  18. ^ Brosh RM, Karmakar P, Sommers JA, Yang Q, Wang XW, Spillare EA, Harris CC, Bohr VA (September 2001). "p53 Modulates the exonuclease activity of Werner syndrome protein". J. Biol. Chem. 276 (37): 35093–102.  
  19. ^ Rodríguez-López AM, Jackson DA, Nehlin JO, Iborra F, Warren AV, Cox LS (February 2003). "Characterisation of the interaction between WRN, the helicase/exonuclease defective in progeroid Werner's syndrome, and an essential replication factor, PCNA". Mech. Ageing Dev. 124 (2): 167–74.  
  20. ^ Huang S, Beresten S, Li B, Oshima J, Ellis NA, Campisi J (June 2000). "Characterization of the human and mouse WRN 3'-->5' exonuclease". Nucleic Acids Res. 28 (12): 2396–405.  
  21. ^ Opresko PL, von Kobbe C, Laine JP, Harrigan J, Hickson ID, Bohr VA (October 2002). "Telomere-binding protein TRF2 binds to and stimulates the Werner and Bloom syndrome helicases". J. Biol. Chem. 277 (43): 41110–9.  
  22. ^ Branzei D, Hayashi T, Suzuki H, Masuko T, Onoda F, Heo SJ, Ikeda H, Shimamoto A, Furuichi Y, Seki M, Enomoto T (June 2001). "A novel protein interacts with the Werner's syndrome gene product physically and functionally". J. Biol. Chem. 276 (23): 20364–9.  

Further reading

  • Comai L, Li B (2004). "The Werner syndrome protein at the crossroads of DNA repair and apoptosis". Mech Ageing Dev 125 (8): 521–8.  
  • Lee JW, Harrigan J, Opresko PL, Bohr VA (2005). "Pathways and functions of the Werner syndrome protein". Mech Ageing Dev 126 (1): 79–86.  
  • Monnat RJ Jr, Saintigny Y (2004). "Werner syndrome protein--unwinding function to explain disease". Sci Aging Knowledge Environ 2004 (13): re3.  
  • Ozgenc A, Loeb LA (2005). "Current advances in unraveling the function of the Werner syndrome protein". Mutat Res 577 (1–2): 237–51.  
  • Swanson C, Saintigny Y, Emond MJ, Monnat RJ Jr (2004). "The Werner syndrome protein has separable recombination and survival functions". DNA Repair (Amst) 3 (5): 475–82.  
  • Moser MJ, Oshima J, Monnat RJ (1999). "WRN mutations in Werner syndrome". Hum. Mutat. 13 (4): 271–9.  
  • Kastan MB, Lim DS (2001). "The many substrates and functions of ATM". Nat. Rev. Mol. Cell Biol. 1 (3): 179–86.  

External links

  • Oshima J, Martin GM, Hisama FM (February 2012). Werner Syndrome.  
  • GeneCard
  • Werner Syndrome Mutational Database
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