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Gene Review

WRN  -  Werner syndrome, RecQ helicase-like

Homo sapiens

Synonyms: DNA helicase, RecQ-like type 3, Exonuclease WRN, RECQ3, RECQL2, RECQL3, ...
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Disease relevance of WRN


Psychiatry related information on WRN


High impact information on WRN

  • Research on the Werner syndrome and a surprising number of other progeroid syndromes support the importance of the maintenance of genomic stability as a partial antidote to aging [9].
  • This suggests that defects in the suppression of rearrangements involving divergent, repeated sequences may underlie the genome instability seen in BLM and WRN patients and in cancer cases associated with defects in these genes [10].
  • Mut-7 of C. elegans, required for transposon silencing and RNA interference, is a homolog of Werner syndrome helicase and RNaseD [11].
  • The premature ageing syndrome protein, WRN, is a 3'-->5' exonuclease [12].
  • Werner syndrome (WS) is an uncommon autosomal recessive disorder characterized by premature aging [13].

Chemical compound and disease context of WRN


Biological context of WRN

  • We found that WRN associates with telomeres when dissociation of telomeric D loops is likely during replication and recombination [19].
  • We show here that WRN functionally interacts with DNA polymerase delta (pol delta), a eukaryotic polymerase required for DNA replication and DNA repair [20].
  • Our findings suggest that WRN may facilitate pol delta-mediated DNA replication and/or DNA repair and that disruption of WRN-pol delta interaction in WS cells may contribute to the previously observed S-phase defects and/or the unusual sensitivity to a limited number of DNA damaging agents [20].
  • In addition, we show that a limited number of haplotypes are associated with the disease in both populations and that these haplotypes define clusters of apparently related haplotypes that may identify as many as eight or nine independent WRN mutations in these two populations [21].
  • Here we present the results of a search for a region that exhibits linkage disequilibrium with the disorder, under the assumption that identification of such a region may provide an alternative method of narrowing down the location of WRN, the gene responsible for WS [21].

Anatomical context of WRN


Associations of WRN with chemical compounds

  • Genetic complementation studies indicate that human WRN rescues dna2-1 mutant phenotypes of growth, cell cycle arrest and sensitivity to the replication inhibitor hydroxyurea or DNA damaging agent methylmethane sulfonate [25].
  • The results demonstrate that BLM and WRN proteins exhibit similar sensitivity profiles to these DNA-binding ligands and are most potently inhibited by the structurally related minor groove binders distamycin A and netropsin (K(i) </=1 microM) [26].
  • The presence of aphidicolin inhibited CPT-induced WRNp foci strongly but not bleomycin-induced foci [27].
  • In pursuit of a functional interaction between WRN and PARP-1, we found that WS cells are deficient in the poly(ADP-ribosyl)ation pathway after they are treated with the DNA-damaging agents H2O2 and methyl methanesulfonate [28].
  • Moreover, Trichostatin A delays the re-entry of WRN into the nucleolus at late times after irradiation [29].

Physical interactions of WRN

  • Werner syndrome protein interacts with human flap endonuclease 1 and stimulates its cleavage activity [3].
  • WRN interacts physically and functionally with the recombination mediator protein RAD52 [30].
  • The Pso4 mRNA splicing and DNA repair complex interacts with WRN for processing of DNA interstrand cross-links [31].
  • In vitro studies also indicate that PCNA binds to a region in the N terminus portion of the WS protein containing a potential 3'-5' exonuclease domain [32].
  • These results indicate that the WRN/PARP-1 complex plays a key role in the cellular response to oxidative stress and alkylating agents, suggesting a role for these proteins in the base excision DNA repair pathway [28].
  • We show that SIRT1 interacts with WRN both in vitro and in vivo; this interaction is enhanced after DNA damage [33].

Enzymatic interactions of WRN

  • Here, we show that WRN is phosphorylated through an ATR/ATM dependent pathway in response to replication blockage [34].
  • WRN is phosphorylated in vivo after treatment of cells with DNA-damaging agents in a pathway that requires DNA-PKcs [35].
  • Exogenous expression of exonuclease domain-deleted WRN interferes with the repair of radiation-induced DNA damages [36].

Co-localisations of WRN

  • BLM is found primarily in nuclear domain 10 except during S phase when it colocalizes with the Werner syndrome gene product, WRN, in the nucleolus [37].
  • In cells arrested in S phase with hydroxyurea, WRN exits the nucleolus and colocalizes with p53 in the nucleoplasm [38].
  • In human cells, we report that WRN co-localizes and physically interacts with the critical telomere maintenance protein TRF2 [39].
  • In response to gamma-irradiation or mitomycin C, WRN leaves the nucleoli and co-localizes with the Mre11 complex in the nucleoplasm [40].
  • Werner's syndrome protein (WRN) migrates Holliday junctions and co-localizes with RPA upon replication arrest [41].

Regulatory relationships of WRN

  • These data support the hypothesis that p53 can induce apoptosis through the modulation of specific DExH-containing DNA helicases and may have implications for the cancer predisposition observed in WS patients [22].
  • WS protein (WRN) dramatically stimulates the rate of FEN-1 cleavage of a 5' flap DNA substrate [3].
  • The exonucleolytic and endonucleolytic cleavage activities of human exonuclease 1 are stimulated by an interaction with the carboxyl-terminal region of the Werner syndrome protein [42].
  • In the 5' upstream region, one Sp1 site and several AP 2 sites exist near the capping site, suggesting that the expression of RECQL4 is regulated by a housekeeping-type promoter similar to WRN [43].
  • Furthermore, WRN RNAi-induced DNA damage was suppressed by overexpression of the telomere-binding protein TRF2 [44].

Other interactions of WRN

  • p53-mediated apoptosis is attenuated in Werner syndrome cells [22].
  • These conditions, however, did not prevent the DNA damage response in BLM-ablated cells, suggesting a distinct role for WRN in DNA homeostasis in vivo [44].
  • Thus, the genomic instability observed in WRN-/- cells may be at least partially attributed to the lack of interactions between the WRN protein and human nucleases including EXO-1 [42].
  • Here we report a novel physical and functional interaction between WRN and the homologous recombination mediator protein RAD52 [30].
  • By comparative Northern blot analysis, we show that the RECQL4 transcripts are severely down-regulated in the cells from RTS patients, similar to our previous observation for WRN transcripts in cells from Werner patients [43].

Analytical, diagnostic and therapeutic context of WRN

  • By using enzyme-linked immunosorbent assay (ELISA) to examine physical interaction between WRN and the same deletion mutants, we found that the WRN-binding motif is located within amino acids 100-300 and overlaps with the single-stranded DNA binding domain (amino acids 150-450) [45].
  • RESULTS: Using immunocytochemistry, we found that WRNp forms distinct nuclear foci in response to DNA damaging agents, including camptothecin (CPT), etoposide, 4-nitroquinolin-N-oxide and bleomycin [27].
  • Like its RecQ helicase family member, WRN, the defective protein in Werner syndrome, dissection of the BLM protein revealed that its HRDC domain is sufficient for its recruitment to the damaged sites [46].
  • Results from coimmunoprecipitation studies indicate that WRN is associated with replication protein A (RPA) and p53 in vivo before and after treatment with the replication inhibitor hydroxyurea or gamma-irradiation that introduces DNA strand breaks [47].
  • Second, the exonuclease co-purifies with the 160-kDa WRN protein and its associated DNA helicase and ATPase activities through successive steps of ion exchange and affinity chromatography, suggesting that all three activities are physically associated [48].


  1. Nucleolar localization of the Werner syndrome protein in human cells. Marciniak, R.A., Lombard, D.B., Johnson, F.B., Guarente, L. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  2. Werner and Bloom helicases are involved in DNA repair in a complementary fashion. Imamura, O., Fujita, K., Itoh, C., Takeda, S., Furuichi, Y., Matsumoto, T. Oncogene (2002) [Pubmed]
  3. Werner syndrome protein interacts with human flap endonuclease 1 and stimulates its cleavage activity. Brosh, R.M., von Kobbe, C., Sommers, J.A., Karmakar, P., Opresko, P.L., Piotrowski, J., Dianova, I., Dianov, G.L., Bohr, V.A. EMBO J. (2001) [Pubmed]
  4. Biochemical analysis of the DNA unwinding and strand annealing activities catalyzed by human RECQ1. Sharma, S., Sommers, J.A., Choudhary, S., Faulkner, J.K., Cui, S., Andreoli, L., Muzzolini, L., Vindigni, A., Brosh, R.M. J. Biol. Chem. (2005) [Pubmed]
  5. RecQ DNA helicase is a suppressor of illegitimate recombination in Escherichia coli. Hanada, K., Ukita, T., Kohno, Y., Saito, K., Kato, J., Ikeda, H. Proc. Natl. Acad. Sci. U.S.A. (1997) [Pubmed]
  6. Helicases and aging. Nakura, J., Ye, L., Morishima, A., Kohara, K., Miki, T. Cell. Mol. Life Sci. (2000) [Pubmed]
  7. Genetic modulation of the senescent phenotype of Homo sapiens. Martin, G.M. Exp. Gerontol. (1996) [Pubmed]
  8. Determination of telomere length by flow-fluorescence in situ hybridization in Down's syndrome patients. Brando, B., Longo, A., Beltrami, B., Passoni, D., Verna, R., Licastro, F., Corsi, M.M. International journal of tissue reactions. (2004) [Pubmed]
  9. Genetic modulation of senescent phenotypes in Homo sapiens. Martin, G.M. Cell (2005) [Pubmed]
  10. SGS1, the Saccharomyces cerevisiae homologue of BLM and WRN, suppresses genome instability and homeologous recombination. Myung, K., Datta, A., Chen, C., Kolodner, R.D. Nat. Genet. (2001) [Pubmed]
  11. Mut-7 of C. elegans, required for transposon silencing and RNA interference, is a homolog of Werner syndrome helicase and RNaseD. Ketting, R.F., Haverkamp, T.H., van Luenen, H.G., Plasterk, R.H. Cell (1999) [Pubmed]
  12. The premature ageing syndrome protein, WRN, is a 3'-->5' exonuclease. Huang, S., Li, B., Gray, M.D., Oshima, J., Mian, I.S., Campisi, J. Nat. Genet. (1998) [Pubmed]
  13. The Werner syndrome protein is a DNA helicase. Gray, M.D., Shen, J.C., Kamath-Loeb, A.S., Blank, A., Sopher, B.L., Martin, G.M., Oshima, J., Loeb, L.A. Nat. Genet. (1997) [Pubmed]
  14. Polymorphisms of the TP53 codon 72 and WRN codon 1367 in individuals from Northern Brazil with gastric adenocarcinoma. Khayat, A.S., Lobo Gatti, L., Moura Lima, E., de Assumpção, P.P., Nascimento Motta, F.J., Harada, M.L., Casartelli, C., Marques Payão, S.L., Cardoso Smith, M.A., Burbano, R.R. Clin. Exp. Med. (2005) [Pubmed]
  15. The Werner syndrome protein confers resistance to the DNA lesions N3-methyladenine and O6-methylguanine: implications for WRN function. Blank, A., Bobola, M.S., Gold, B., Varadarajan, S., D Kolstoe, D., Meade, E.H., Rabinovitch, P.S., Loeb, L.A., Silber, J.R. DNA Repair (Amst.) (2004) [Pubmed]
  16. Instability of the fragile X syndrome repeat in mice: the effect of age, diet and mutations in genes that affect DNA replication, recombination and repair proficiency. Fleming, K., Riser, D.K., Kumari, D., Usdin, K. Cytogenet. Genome Res. (2003) [Pubmed]
  17. Detection by epitope-defined monoclonal antibodies of Werner DNA helicases in the nucleoplasm and their upregulation by cell transformation and immortalization. Shiratori, M., Sakamoto, S., Suzuki, N., Tokutake, Y., Kawabe, Y., Enomoto, T., Sugimoto, M., Goto, M., Matsumoto, T., Furuichi, Y. J. Cell Biol. (1999) [Pubmed]
  18. A polymorphic variant at the Werner helicase (WRN) gene is associated with bone density, but not spondylosis, in postmenopausal women. Ogata, N., Shiraki, M., Hosoi, T., Koshizuka, Y., Nakamura, K., Kawaguchi, H. J. Bone Miner. Metab. (2001) [Pubmed]
  19. The Werner syndrome helicase and exonuclease cooperate to resolve telomeric D loops in a manner regulated by TRF1 and TRF2. Opresko, P.L., Otterlei, M., Graakjaer, J., Bruheim, P., Dawut, L., Kølvraa, S., May, A., Seidman, M.M., Bohr, V.A. Mol. Cell (2004) [Pubmed]
  20. Functional interaction between the Werner Syndrome protein and DNA polymerase delta. Kamath-Loeb, A.S., Johansson, E., Burgers, P.M., Loeb, L.A. Proc. Natl. Acad. Sci. U.S.A. (2000) [Pubmed]
  21. Linkage disequilibrium and haplotype studies of chromosome 8p 11.1-21.1 markers and Werner syndrome. Yu, C.E., Oshima, J., Goddard, K.A., Miki, T., Nakura, J., Ogihara, T., Poot, M., Hoehn, H., Fraccaro, M., Piussan, C. Am. J. Hum. Genet. (1994) [Pubmed]
  22. p53-mediated apoptosis is attenuated in Werner syndrome cells. Spillare, E.A., Robles, A.I., Wang, X.W., Shen, J.C., Yu, C.E., Schellenberg, G.D., Harris, C.C. Genes Dev. (1999) [Pubmed]
  23. Telomere instability in a human tumor cell line expressing a dominant-negative WRN protein. Bai, Y., Murnane, J.P. Hum. Genet. (2003) [Pubmed]
  24. Expression of the BLM gene in human haematopoietic cells. Kaneko, H., Matsui, E., Fukao, T., Kasahara, K., Morimoto, W., Kondo, N. Clin. Exp. Immunol. (1999) [Pubmed]
  25. In vivo function of the conserved non-catalytic domain of Werner syndrome helicase in DNA replication. Sharma, S., Sommers, J.A., Brosh, R.M. Hum. Mol. Genet. (2004) [Pubmed]
  26. Potent inhibition of werner and bloom helicases by DNA minor groove binding drugs. Brosh, R.M., Karow, J.K., White, E.J., Shaw, N.D., Hickson, I.D., Bohr, V.A. Nucleic Acids Res. (2000) [Pubmed]
  27. Werner helicase relocates into nuclear foci in response to DNA damaging agents and co-localizes with RPA and Rad51. Sakamoto, S., Nishikawa, K., Heo, S.J., Goto, M., Furuichi, Y., Shimamoto, A. Genes Cells (2001) [Pubmed]
  28. Central role for the Werner syndrome protein/poly(ADP-ribose) polymerase 1 complex in the poly(ADP-ribosyl)ation pathway after DNA damage. von Kobbe, C., Harrigan, J.A., May, A., Opresko, P.L., Dawut, L., Cheng, W.H., Bohr, V.A. Mol. Cell. Biol. (2003) [Pubmed]
  29. DNA damage-induced translocation of the Werner helicase is regulated by acetylation. Blander, G., Zalle, N., Daniely, Y., Taplick, J., Gray, M.D., Oren, M. J. Biol. Chem. (2002) [Pubmed]
  30. WRN interacts physically and functionally with the recombination mediator protein RAD52. Baynton, K., Otterlei, M., Bjørås, M., von Kobbe, C., Bohr, V.A., Seeberg, E. J. Biol. Chem. (2003) [Pubmed]
  31. The Pso4 mRNA splicing and DNA repair complex interacts with WRN for processing of DNA interstrand cross-links. Zhang, N., Kaur, R., Lu, X., Shen, X., Li, L., Legerski, R.J. J. Biol. Chem. (2005) [Pubmed]
  32. The Werner syndrome gene product co-purifies with the DNA replication complex and interacts with PCNA and topoisomerase I. Lebel, M., Spillare, E.A., Harris, C.C., Leder, P. J. Biol. Chem. (1999) [Pubmed]
  33. Regulation of WRN protein cellular localization and enzymatic activities by SIRT1-mediated deacetylation. Li, K., Casta, A., Wang, R., Lozada, E., Fan, W., Kane, S., Ge, Q., Gu, W., Orren, D., Luo, J. J. Biol. Chem. (2008) [Pubmed]
  34. Werner's syndrome protein is phosphorylated in an ATR/ATM-dependent manner following replication arrest and DNA damage induced during the S phase of the cell cycle. Pichierri, P., Rosselli, F., Franchitto, A. Oncogene (2003) [Pubmed]
  35. Werner protein is a target of DNA-dependent protein kinase in vivo and in vitro, and its catalytic activities are regulated by phosphorylation. Karmakar, P., Piotrowski, J., Brosh, R.M., Sommers, J.A., Miller, S.P., Cheng, W.H., Snowden, C.M., Ramsden, D.A., Bohr, V.A. J. Biol. Chem. (2002) [Pubmed]
  36. Exogenous expression of exonuclease domain-deleted WRN interferes with the repair of radiation-induced DNA damages. Kashino, G., Kodama, S., Suzuki, K., Matsumoto, T., Watanabe, M. J. Radiat. Res. (2005) [Pubmed]
  37. Nuclear structure in normal and Bloom syndrome cells. Yankiwski, V., Marciniak, R.A., Guarente, L., Neff, N.F. Proc. Natl. Acad. Sci. U.S.A. (2000) [Pubmed]
  38. p53 Modulates the exonuclease activity of Werner syndrome protein. Brosh, R.M., Karmakar, P., Sommers, J.A., Yang, Q., Wang, X.W., Spillare, E.A., Harris, C.C., Bohr, V.A. J. Biol. Chem. (2001) [Pubmed]
  39. Telomere-binding protein TRF2 binds to and stimulates the Werner and Bloom syndrome helicases. Opresko, P.L., von Kobbe, C., Laine, J.P., Harrigan, J., Hickson, I.D., Bohr, V.A. J. Biol. Chem. (2002) [Pubmed]
  40. Linkage between Werner syndrome protein and the Mre11 complex via Nbs1. Cheng, W.H., von Kobbe, C., Opresko, P.L., Arthur, L.M., Komatsu, K., Seidman, M.M., Carney, J.P., Bohr, V.A. J. Biol. Chem. (2004) [Pubmed]
  41. Werner's syndrome protein (WRN) migrates Holliday junctions and co-localizes with RPA upon replication arrest. Constantinou, A., Tarsounas, M., Karow, J.K., Brosh, R.M., Bohr, V.A., Hickson, I.D., West, S.C. EMBO Rep. (2000) [Pubmed]
  42. The exonucleolytic and endonucleolytic cleavage activities of human exonuclease 1 are stimulated by an interaction with the carboxyl-terminal region of the Werner syndrome protein. Sharma, S., Sommers, J.A., Driscoll, H.C., Uzdilla, L., Wilson, T.M., Brosh, R.M. J. Biol. Chem. (2003) [Pubmed]
  43. Rothmund-thomson syndrome responsible gene, RECQL4: genomic structure and products. Kitao, S., Lindor, N.M., Shiratori, M., Furuichi, Y., Shimamoto, A. Genomics (1999) [Pubmed]
  44. Werner protein protects nonproliferating cells from oxidative DNA damage. Szekely, A.M., Bleichert, F., Nümann, A., Van Komen, S., Manasanch, E., Ben Nasr, A., Canaan, A., Weissman, S.M. Mol. Cell. Biol. (2005) [Pubmed]
  45. The N-terminal domain of the large subunit of human replication protein A binds to Werner syndrome protein and stimulates helicase activity. Shen, J.C., Lao, Y., Kamath-Loeb, A., Wold, M.S., Loeb, L.A. Mech. Ageing Dev. (2003) [Pubmed]
  46. BLM is an early responder to DNA double-strand breaks. Karmakar, P., Seki, M., Kanamori, M., Hashiguchi, K., Ohtsuki, M., Murata, E., Inoue, E., Tada, S., Lan, L., Yasui, A., Enomoto, T. Biochem. Biophys. Res. Commun. (2006) [Pubmed]
  47. p53 modulates RPA-dependent and RPA-independent WRN helicase activity. Sommers, J.A., Sharma, S., Doherty, K.M., Karmakar, P., Yang, Q., Kenny, M.K., Harris, C.C., Brosh, R.M. Cancer Res. (2005) [Pubmed]
  48. Werner syndrome protein. I. DNA helicase and dna exonuclease reside on the same polypeptide. Shen, J.C., Gray, M.D., Oshima, J., Kamath-Loeb, A.S., Fry, M., Loeb, L.A. J. Biol. Chem. (1998) [Pubmed]
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