Werner syndrome: Molecular insights into the relationships between defective DNA metabolism, genomic instability, cancer and aging

Frontiers in Bioscience

Volumn 11, Issue SUPPL. 2, 2006, Pages 2657-2671

  Orren, David K ^a  

^a UNIVERSITY OF KENTUCKY   (United States)

Author keywords

Aging; Apoptosis; Cancer; Genomic Instability; RecQ helicases; Review; Senescence; Telomeres; Werner syndrome

Indexed keywords

EID: 33744496790     PISSN: 27686701     EISSN: 27686698     Source Type: Journal    
DOI: 10.2741/1999     Document Type: Review

References (146)

1. O. Werner: Uber katarakt in verbindung mit sklerodermie. Doctoral dissertation, Kiel University, Schmidt and Klauning (1904)
2. M. Goto: Hierarchical deterioration of body systems in Werner's syndrome: implications for normal ageing. Mech. Ageing Dev. 98(3), 239-254 (1997)
3. G. M. Martin and J. Oshima: Lessons from human progeroid syndromes. Nature 408(6809), 263-266 (2000)
4. M. Goto, M. Rubenstein, J. Weber, K. Woods and D. Drayna: Genetic linkage of Werner's syndrome to five markers on chromosome 8. Nature 355(6362), 735-738 (1992)
5. C.-E. Yu, J. Oshima, Y. H. Fu, E. M. Wijsman, F. Hisama, R. Alisch, S. Matthews, J. Nakura, T. Miki, S. Ouais, G. M. Martin, J. Mulligan and G. D. Schellenberg: Positional cloning of the Werner's syndrome gene. Science 272(5259), 258-262 (1996)
6. J. Oshima, C.-E. Yu, C. Piussan, G. Klein, J. Jabkowski, S. Balci, T. Miki, J. Nakura, T. Ogihara, J. Ells, M. Smith, M. I. Melaragno, M. Fraccaro, S. Scappaticci, J. Matthews, S. Ouais, A. Jarzebowicz, G. D. Schellenberg and G. M. Martin: Homozygous and compound heterozygous mutations at the Werner syndrome locus. Hum. Mol. Genet. 5(12), 1909-1913 (1996)
7. C.-E. Yu, J. Oshima, E. M. Wijsman, J. Nakura, T. Miki, C. Piussan, S. Matthews, Y. H. Fu, J. Mulligan, G. M. Martin and G. D. Schellenberg: Mutations in the consensus helicase domains of the Werner syndrome gene. Am. J. Hum. Genet. 60(2), 330-341 (1997)
8. T. Matsumoto, A. Shimamoto, M. Goto and Y. Furuichi: Impaired nuclear localization of defective DNA helicases in Werner's syndrome. Nat. Genet. 16(4), 335-336 (1997)
9. R. A. Marciniak, D. B. Lombard, F. B. Johnson and L. Guarente: Nucleolar localization of the Werner syndrome protein in human cells. Proc. Natl. Acad. Sci. USA 95(12), 6887-6892 (1998)
10. C. E. Ogburn, J. Oshima, M. Poot, R. Chen, K. E. Hunt, K. A. Gollahon, P. S. Rabinovitch and G. M. Martin: An apoptosis-inducing genotoxin differentiates heterozygotic carriers for Werner helicase mutations from wild-type and homozygous mutants. Hum Genet. 101(2), 121-125 (1997)
11. L. Ye, T. Miki, J. Nakura, J. Oshima, K. Kamino, H. Rakugi, H. Ikegami, J. Higaki, S. D. Edland, G. M. Martin and T. Ogihara: Association of a polymorphic variant of the Werner helicase gene with myocardial infarction in a Japanese population. Am. J. Hum. Genet. 68(4), 494-498 (1997)
12. N. Ogata, M. Shiraki, T. Hosoi, Y. Koshizuka, K. Nakamura and H. Kawaguichi: A polymorphic variant at the Werner helicase (WRN) gene is associated with bone density, but not spondylosis, in postmenopausal women. J. Bone Mineral Metab. 19(5), 296-301 (2001)
13. V. A. Bohr, E. J. Metter, J. A. Harrigan, C. von Kobbe, J. L. Liu, M. D. Gray, A. Majumdar, D. M. Wilson III and M. M. Seidman: Werner syndrome protein 1367 variants and disposition towards coronary artery disease in Caucasian patients. Mech. Ageing Dev. 125(7), 491-496 (2004)
14. N. A. Ellis, J. Groden, T.-Z. Ye, J. Straughen, D. J. Lennon, S. Ciocci, M. Proytcheva and J. German: The Bloom's syndrome gene product is homologous to RecQ helicases. Cell 83(4), 655-666 (1995)
15. S. Kitao, A. Shimamoto, M. Goto, R. W. Miller, W. A. Smithson, N. M. Lindor and Y. Furuichi: Mutations in REQL4 cause a subset of cases of Rothmund-Thomson syndrome. Nat. Genet. 22(1), 82-84 (1999)
16. H. A. Siitonen, O. Kopra, H. Kaariainen, H. Haravuori, R. M. Winter, A. M. Saamanen, L. Peltonen and M. Kestila: Molecular defect of the RAPADILINO syndrome expands the phenotype spectrum of REQL diseases. Hum. Mol. Genet. 12(21), 2837-2844 (2003)
17. L. van Maldergem, H. A. Siitonen, N. Jalkh, E. Chouery, M. de Roy, V. Delague, M. Muenke, E. W. Jabs, J. L. Cai, L. L. Wang, S. E. Plon, C. Fourneau, M. Kestila, Y. Gillerot, A. Megarbane and A. Verloes: Revisiting the craniosynostosis-radial ray hypoplasia association: Baller-Gerold syndrome caused by mutations in the RECQL4 gene. J. Med. Genet. 43(2), 148-152 (2006)
18. D. A. Bernstein, M. C. Zittel and J. L. Keck: High-resolution structure of the E. coli RecQ helicase catalytic core. EMBO J. 22(19), 4910-4921 (2003)
19. Z. Liu, M. J. Macias, M. J. Bottomley, G. Stier, J. P. Linge, M. Nilges, P. Bork and M. Sattler: The three-dimensional structure of the HRDC domain and implications for the Werner and Bloom syndrome proteins. Structure 7(12), 1557-1566 (1999)
20. C. von Kobbe, N. H. Thoma, B. K. Czyzewski, N. P. Pavletich and V. A. Bohr: Werner syndrome protein contains three structure-specific DNA binding domains. J. Biol. Chem. 278(52), 52997-53006 (2003)
21. J.-S. Hu, H. Feng, W. Zeng, G.-X. Lin and X.-G. Xi: Solution structure of a multifunctional DNA- and protein-binding motif of human Werner syndrome protein. Proc. Natl. Acad. Sci. USA 102(51), 18379-18384 (2005)
22. J. W. Lee, R. Kusumoto, K. M. Doherty, G.-X. Lin, W. Zeng, W.-H. Cheng, C. von Kobbe, R. M. Brosh, Jr, J.-S. Hu and V. A. Bohr: Modulation of Werner syndrome protein function by a single mutation in the conserved RecQ domain. J. Biol. Chem. 280(47), 39627-39636 (2005)
23. I. S. Mian: Comparative sequence analysis of ribonucleases HII, III, II, PH and D. Nucleic Acids Res. 25(16), 3187-3195 (1997)
24. M. Lebel and P. Leder: A deletion within the murine Werner syndrome helicase induces sensitivity to inhibitors of topoisomerase and loss of cellular proliferative capacity. Proc. Natl. Acad. Sci. USA 95(22), 13097-13102 (1998)
25. H. Yan, C.-Y. Chen, R. Kobayashi and J. Newport: Replication focus-forming activity 1 and the Werner syndrome gene product Nat. Genet. 19(4), 375-378 (1998)
26. B. Li, N. Conway, S. Navarro, L. Comai and L. Comai: A conserved and species-specific functional interaction between the Werner syndrome-like exonuclease atWEX and the Ku heterodimer in Arabidopsis. Nucleic Acids Res. 33(21), 6861-6867 (2005)
27. M. D. Gray, J.-C. Shen, A. S. Kamath-Loeb, A. Blank, B. L. Sopher, G. M. Martin, J. Oshima and L. A. Loeb: The Werner syndrome protein is a DNA helicase. Nat. Genet. 17(1), 100-103 (1997)
28. A. S. Kamath-Loeb, P. Welcsh, M. Waite, E. T. Adman and L. A. Loeb: The enzymatic activities of the Werner syndrome protein are disabled by the amino acid polymorphism R834C. J. Biol. Chem. 279(53), 55499-55505 (2004)
29. D. K. Orren, R. M. Brosh, Jr., J. O. Nehlin, A. Machwe, M. D. Gray and V. A. Bohr: Enzymatic and DNA binding properties of purified WRN protein: high affinity binding to single-stranded DNA but not to DNA damaged by 4NQO. Nucleic Acids Res. 27(17), 3557-3566.
30. J.-C. Shen, M. D. Gray, J. Oshima and L. A. Loeb: Characterization of Werner syndrome protein DNA helicase activity: directionality, substrate dependence and stimulation by replication protein A. Nucleic Acids Res. 26(12), 2879-2885 (1998)
31. P. Mohaghegh, J. K. Karow, R. M. Brosh, Jr., V. A. Bohr and I. D. Hickson: The Bloom's and Werner's syndrome proteins are DNA structure-specific helicases. Nucleic Acids Res. 29(13), 2843-2849 (2001)
32. R. M. Brosh, Jr., A. Majumdar, S. Desai, I. D. Hickson, V. A. Bohr and M. M. Seidman: Unwinding of a DNA triple helix by the Werner and Bloom syndrome helicases. J. Biol. Chem. 276(5), 3024-3030 (2001)
33. R. M. Brosh, Jr., J. Waheed and J. A. Sommers: Biochemical characterization of the DNA substrate specificity of Werner syndrome helicase. J. Biol. Chem. 277(26), 23236-23245 (2002)
34. D. K. Orren, S. Theodore and A. Machwe: The Werner syndrome helicase/exonuclease (WRN) disrupts and degrades D-loops in vitro. Biochemistry 41(46), 13483-13488 (2002)
35. n. J. Biol. Chem. 274(18), 12797-12802 (1999)
36. A. Constantinou, M. Tarsounas, J. K. Karow, R. M. Brosh, V. A. Bohr, I. D. Hickson and S. C. West: Werner's syndrome protein (WRN) migrates Holliday junctions and co-localizes with RPA upon replication arrest. EMBO Rep. 1(1), 80-84 (2000)
37. R. M. Brosh, Jr., D. K. Orren, J. O. Nehlin, P. H. Ravn, M. K. Kenny, A. Machwe and V. A. Bohr: Functional and physical interaction between WRN helicase and human replication protein A. J. Biol. Chem. 274(26), 18241-18350 (1999)
38. Q. Yang, R. Zhang, X. W. Wang, E. A. Spillare, S. P. Linke, D. Subramanian, J. D. Griffith, J. L. Li, I. D. Hickson, J. C. Shen, L. A. Loeb, S. J. Mazur, E. Appella, R. M. Brosh, Jr., P. Karmakar, V. A. Bohr and C. C. Harris: The processing of Holliday junctions by BLM and WRN helicases is regulated by p53. J. Biol. Chem. 277(35), 31980-31987 (2002)
39. P. L. Opresko, C. von Kobbe, J.-P. Laine, J. Harrigan, I. D. Hickson and V. A. Bohr: Telomere-binding protein TRF2 binds to and stimulates the Werner and Bloom syndrome helicases. J. Biol. Chem. 277(43), 41110-41119 (2002)
40. K. Baynton, M. Otterlei, M. Bjoras, C. von Kobbe, V. A. Bohr and E. Seeberg: WRN interacts physically and functionally with the recombination mediator protein RAD52. J. Biol. Chem. 278(38), 36476-36486
41. P. L. Opresko, P. A. Mason, E. R. Podell, M. Lei, I. D. Hickson, T. R. Cech and V. A. Bohr: POT1 stimulates RecQ helicases WRN and BLM to unwind telomeric DNA substrates. J. Biol. Chem. 280(37), 32069-32080 (2005)
42. A. Machwe, L. Xiao, J. Groden, S. W. Matson and D. K. Orren: RecQ family members combine strand pairing and unwinding activities to catalyze strand exchange. J. Biol. Chem. 280(24), 23397-23407 (2005)
43. P. L. Garcia, Y. Liu, J. Jiricny, S. C. West and P. Janscak: Human RECQ5β, a protein with DNA helicase and strand-annealing activities in a single polypeptide. EMBO J. 23(14), 2882-2891 (2004)
44. C. F. Cheok, L. Wu, P. L. Garcia, P. Janscak and I. D. Hickson: The Bloom's syndrome helicase promotes the annealing of complementary single-stranded DNA. Nucleic Acids Res. 33(12), 3932-3941 (2005)
45. S. Sharma, J. A. Sommers, S. Choudhary, J. K. Faulkner, S. Cui, L. Andreoli, L. Muzzolini, A. Vindigni and R. M. Brosh, Jr: Biochemical analysis of the DNA unwinding and strand annealing activities catalyzed by human RECQ1. J. Biol. Chem. 280(30), 28072-28084 (2005)
46. A. Machwe, E. M. Lozada, L. Xiao and D. K. Orren: Competition between the unwinding and strand pairing activities of the Werner and Bloom syndrome proteins. BMC Mol. Biol. 7(1), 1 (2006)
47. S. Huang, B. Li, M. D. Gray, J. Oshima, I. S. Mian and J. Campisi: The premature ageing syndrome protein, WRN, is a 3′ → 5′ exonuclease. Nat. Genet. 20(2), 114-116 (1998)
48. J.-C. Shen, M. D. Gray, J. Oshima, A. S. Kamath-Loeb, M. Fry and L. A. Loeb: Werner syndrome protein. I. DNA helicase and DNA exonuclease reside on the same polypeptide. J. Biol. Chem. 273(51), 34139-34144 (1998)
49. A. S. Kamath-Loeb, J.-C. Shen, L. A. Loeb and M. Fry: Werner syndrome protein. II. Characterization of the integral 3′ → 5′ DNA exonuclease. J. Biol. Chem. 273(51), 34145-34150 (1998)
50. J.-C. Shen and L. A. Loeb: Werner syndrome exonuclease catalyzes structure-dependent degradation of DNA. Nucleic Acids Res. 28(17), 3260-3268 (2000)
51. A. Machwe, L. Xiao, S. Theodore and D. K. Orren: DNase I footprinting and enhanced exonuclease function of the bipartite Werner syndrome protein (WRN) bound to partially melted duplex DNA. J. Biol. Chem. 277(6), 4492-4504 (2002)
52. S. Huang, S. Beresten, B. Li, J. Oshima, N. A. Ellis and J. Campisi: Characterization of the human and mouse WRN 3′→5′ exonuclease. Nucleic Acids Res. 28(12), 2396-2405 (2000)
53. Y. Xue, G. C. Ratcliff, H. Wang, P. R. Davis-Searles, M. D. Gray, D. A. Erie and M. R. Redinbo: A minimal exonuclease domain of WRN forms a hexamer on DNA and possesses both 3′→5′ exonuclease and 5′-protruding strand endonuclease activities. Biochemistry 41(9), 2901-2912 (2002)
54. M. P. Cooper, A. Machwe, D. K. Orren, D. Ramsden and V. A. Bohr: Ku complex interacts with and stimulates the Werner protein. Genes Dev. 14(8), 907-912 (2000)
55. B. Li and L. Comai: Functional interaction between Ku and the Werner syndrome protein in DNA end processing. J. Biol. Chem. 275(37), 28349-28352 (2000)
56. J. Friedemann, F. Grosse and S. Zhang: Nuclear DNA helicase II (RNA helicase A) interacts with Werner syndrome helicase and stimulates its exonuclease activity. J. Biol. Chem. 280(35), 31303-31313 (2005)
57. A. Machwe, R. Ganunis, V. A. Bohr and D. K. Orren. Selective blockage of the 3′→ 5′ exonuclease activity of WRN protein by certain oxidative modifications and bulky lesions in DNA. Nucleic Acids Res. 28(14), 2762-2770 (2000)
58. D. K. Orren, A. Machwe, P. Karmakar, J. Piotrowski, M. P. Cooper and V. A. Bohr (2001). A functional interaction of Ku with Werner exonuclease facilitates digestion of damaged DNA. Nucleic Acids Res. 29(9), 1926-1934 (2001)
59. A. Machwe, L. Xiao and D. K. Orren: TRF2 recruits the Werner syndrome exonuclease for processing telomeric DNA. Oncogene 23(1), 149-156 (2004)
60. R. M. Brosh, Jr., P. Karmakar, J. A. Sommers, Q. Yang, X. W. Wang, E. A. Spillare, C. C. Harris and V. A. Bohr: p53 modulates the exonuclease activity of Werner syndrome protein. J. Biol. Chem. 276(37), 35093-35102 (2001)
61. C. von Kobbe, P. Karmakar, L. Dawut, P. Opresko, X. Zeng, R. M. Brosh, Jr., I. D. Hickson and V. A. Bohr: Colocalization, physical, and functional interaction between Werner and Bloom syndrome proteins. J. Biol. Chem. 277(24), 22035-22044 (2002)
62. A. Machwe, L. Xiao and D. K. Orren: Length-dependent degradation of single-stranded 3′ ends by the Werner syndrome protein (WRN): implications for spatial orientation and coordinated 3′ to 5′ movement of its ATPase/helicase and exonuclease domains. BMC Mol. Biol. 7(1), 6 (2006)
63. D. A. Bernstein and J. L. Keck: Domain mapping of Escherichia coli RecQ defines the roles of conserved N-and C-terminal regions in the RecQ family. Nucleic Acids Res. 31(11), 2778-2785 (2003)
64. P. Janscak, P. L. Garcia, F. Hamburger, Y. Makuta, K. Shirashi, Y. Imai, H. Ikeda and T. A. Bickle: Characterization and mutational analysis of the RecQ core of the Bloom syndrome protein. J. Mol. Biol. 330(1), 29-42 (2003)
65. S. M. Yannone, S. Roy, D. W. Chen, M. B. Murphy, S. Huang, J. Campisi and D. J. Chen: Werner syndrome protein is regulated and phosphorylated by DNA-dependent protein kinase. J. Biol. Chem. 276(41), 38242-38248 (2001)
66. G. Blander, N. Zalle, Y. Daniely, J. Taplick, M. D. Gray and M. Oren: DNA damage-induced translocation of the Werner helicase is regulated by acetylation. J. Biol. Chem. 277(52), 50934-50940 (2002)
67. P. Karmakar, J. Piotrowski, R. M. Brosh, Jr., J. A. Sommers, S. P. Miller, W. H. Cheng, C. M. Snowden, D. A. Ramsden and V. A. Bohr: 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), 18291-18302 (2002)
68. P. Pichierri, F. Rosselli and A. Franchitto: 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. Oncogene 22(10), 1491-1500 (2003)
69. P. Karmakar and V. A. Bohr: Cellular dynamics and modulation of WRN protein is DNA damage specific. Mech. Ageing Dev. 126(11), 1146-1158 (2005)
70. E. U. Kurz and S. P. Lees-Miller: DNA damage-induced activation of ATM and ATM-dependent signaling pathways. DNA Repair 3(8-9), 889-900 (2004)
71. S.-T. Kim, D.-S. Lim, C. E. Canman and M. B. Kastan: Substrate specificities and identification of putative substrates of ATM kinase family members. J. Biol. Chem. 274(53), 37538-37543 (1999)
72. Y. Kawabe, M. Seki, T. Seki, W.-S. Wang, O. Imamura, Y. Furuichi, H. Saitoh and T. Enomoto: Covalent modification of the Werner's syndrome gene product with the ubiquitin-related protein, SUMO-1. J. Biol. Chem. 275(28), 20963-20966 (2000)
73. M. D. Gray, L. Wang, H. Youssoufian, G. M. Martin and J. Oshima: Werner helicase is localized to transcriptionally active nucleoli of cycling cells. Exp. Cell Res. 242(2), 487-494 (1998)
74. A. M. Rodriguez-Lopez, D. A. Jackson, F. Iborra and L. S. Cox: Asymmetry of DNA replication fork progression in Werner's syndrome. Aging Cell 1(1), 30-39 (2002)
75. A. M. Rodriguez-Lopez, D. A. Jackson, J. O. Nehlin, F. Iborra, A. V. Warren and L. S. Cox: Characterization 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), 167-174 (2003)
76. T. Suzuki, M. Shiratori, Y. Furuichi and T. Matsumoto: Diverged nuclear localization of Werner helicase in human and mouse cells. Oncogene 20(20), 2551-2558 (2001)
77. S. Sakamoto, K. Nishikawa, S.-J. Heo, M. Goto, Y. Furuichi and A. Shimamoto: Werner helicase relocates into nuclear foci in response to DNA damaging agents and colocalizes with RPA and Rad51. Genes Cells 6(5), 421-430 (2001)
78. A. Franchitto and P. Pichierri: Werner syndrome protein and the MRE11 complex are involved in a common pathway of replication fork recovery. Cell Cycle 3 (10), e78-e86 (2004)
79. W. H. Cheng, S. Sakamoto, J. T. Fox, K. Komatsu, J. Carney and V. A. Bohr: Werner syndrome protein associates with gamma H2AX in a manner that depends upon Nbs1. FEBS Lett. 579(6), 135-1356 (2005)
80. D. Salk, K. Au, H. Hoehn and G. M. Martin: Cytogenetics of Werner syndrome cultured skin fibroblasts: variegated translocation mosaicism. Cytogenet. Cell Genet. 30(2), 92-107 (1981)
81. E. Gebhart, R. Bauer, U. Raub, M. Schinzel, K. W. Ruprecht and J. B. Jonas: Spontaneous and induced chromosomal instability in Werner syndrome. Hum. Genet. 80(2), 135-139 (1988)
82. K.-I. Fukuchi, G. M. Martin and R. J. Monnat, Jr.: Mutator phenotype of Werner syndrome is characterized by extensive deletions. Proc. Natl. Acad. Sci. USA 86(15), 5893-5897 (1989)
83. R. Elli, L. Chessa, A. Antonelli, P. Petrinelli, R. Ambra and L. Marcucci: Effects of topoisomerase II inhibition in lymphoblasts from patients with progeroid and "chromosome instability" syndromes. Cancer Genet. Cytogenet. 87(2), 112-116 (1996)
84. P. Pichierri, A. Franchitto, P. Mosesso and F. Palitti: Werner's syndrome protein is required for correct recovery after replication arrest and DNA damage induced in S-phase of cell cycle. Mol. Biol. Cell 12(8), 2412-2421 (2001)
85. M. Okada, M. Goto, Y. Furuichi and M. Sugimoto: Differential effects of cytotoxic drugs on mortal and immortalized B-lymphoblastoid cell lines from normal and Werner's syndrome patients. Biol. Pharm. Bull. 21(3), 235-239 (1998)
86. M. Poot, K. A. Gollahon and P. S. Rabinovitch: Werner syndrome lymphoblastoid cells are sensitive to camptothecin-induced apoptosis in S-phase. Hum. Genet. 104(1), 10-14 (1999)
87. M. Poot, J. S. Yom, S. H. Whang, J. T. Kato, K. A. Gollahon and P. S. Rabinovitch: Werner syndrome cells are sensitive to DNA cross-linking drugs. FASEB J. 15(7), 1224-1226 (2001)
88. 6-methylguanine: implications for WRN function. DNA Repair 3(6), 629-638 (2004)
89. C. Swanson, Y. Saintigny, M. J. Emond and R. J. Monnat, Jr.: The Werner syndrome protein has separable recombination and survival functions. DNA Repair 3(5), 475-482 (2004)
90. Y. Fujiwara, T. Higashikawa and M. Tatsumi: A retarded rate of DNA replication and normal level of DNA repair in Werner's syndrome fibroblasts in culture. J. Cell Physiol. 92(3), 365-374 (1977)
91. Y. Saintigny, K. Makienko, C. Swanson, M. J. Emond and R. J. Monnat, Jr.: Homologous recombination resolution defect in Werner syndrome. Mol. Cell. Biol. 22(20), 6971-6978 (2002)
92. F. Takeuchi, F. Hanaoka, M. Goto, M. Yamada and T. Miyamoto: Prolongation of S phase and whole cell cycle in Werner's syndrome fibroblasts. Exp. Gerontol. 17(6), 473-480 (1982)
93. M. Poot, H. Hoehn, T. M. Runger and G. M. Martin: Impaired S-phase transit of Werner syndrome cells expressed in lymphoblastoid cell lines. Exp. Cell Res. 202(2), 267-273 (1992)
94. F. Takeuchi, F. Hanaoka, M. Goto, I. Akaoka, T. Hori, M. Yamada and T. Miyamoto: Altered frequency of initiation sites of DNA replication in Werner's syndrome cells. Hum. Genet. 60(4), 365-368 (1982)
95. M. Lebel, E. A. Spillare, C. C. Harris and P. Leder: The Werner syndrome gene product co-purifies with the DNA replication complex and interacts with PCNA and topoisomerase I. J. Biol. Chem. 274(53), 37795-37799 (1999)
96. A. S. Kamath-Loeb, E. Johansson, P. M. J. Burgers and L. A. Loeb: Functional interaction between the Werner syndrome protein and DNA polymerase δ. Proc. Natl. Acad. Sci. USA 97(9), 4603-4608 (2000)
97. R. M. Brosh, Jr., C. von Kobbe, J. A. Sommers, P. Karmakar, P. L. Opresko, J. Piotrowski, I. Dianova, G. L. Dianov and V. A. Bohr: Werner syndrome protein interacts with human flap endonuclease I and stimulates its cleavage activity. EMBO J. 20(20), 5791-5801 (2001)
98. C.-Y. Chen, J. Graham and H. Yan: Evidence for a replication function of FFA-1, the Xenopus orthologue of Werner syndrome protein. J. Cell Biol. 152(5), 985-996 (2001)
99. T. Kawabe, N. Tsuyama, S. Kitao, K. Nishikawa, A. Shimamoto, M. Shiratori, T. Matsumoto, K. Anno, T. Sato, Y. Mitsui, M. Seki, T. Enomoto, M. Goto, N. A. Ellis, T. Ide, Y. Furuichi and M. Sugimoto: Differential regulation of human RecQ family helicases in cell transformation and cell cycle. Oncogene 19(41), 4764-4772 (2000)
100. T. M. Runger, C. Bauer, B. Dekant, K. Moller, P. Sobotta, C. Czerny, M. Poot and G. M. Martin: Hypermutable ligation of plasmid DNA ends in cells from patients with Werner syndrome. J. Invest. Dermatol. 102(1), 45-48 (1994)
101. J. Oshima, S. Huang, J. Campisi and R. H. Schiestl: Lack of WRN results in extensive deletion at nonhomologous joining ends. Cancer Res. 62(2), 547-551 (2002)
102. B. Li and L. Comai: Displacement of DNA-PKcs from DNA ends by the Werner syndrome protein. Nucleic Acids Res. 30(17), 3653-3661 (2002)
103. M. Lebel, J. Lavoie, I. Gaudreault, M. Bronsard and R. Drouin: Genetic cooperation between the Werner syndrome protein and poly(ADP-ribose) polymerase-1 in preventing chromatid breaks, complex chromosomal rearrangements, and cancer in mice. Am. J. Pathol. 162(5), 1559-1569 (2003)
104. C. von Kobbe, J. A. Harrigan, A. May, P. L. Opresko, L. Dawut, W.-H. Cheng, and V. A. Bohr: Central role for the Werner syndrome protein/poly(ADP- ribose) polymerase I complex in the poly(ADP-ribosyl)ation pathway after DNA damage. Mol. Cell. Biol. 23(23), 8601-8613 (2003)
105. B. Li, S. Navarro, N. Kasahara and L. Comai: Identification and biochemical characterization of a Werner's syndrome protein complex with Ku70/80 and poly(ADP-ribose) polymerase-1. J. Biol. Chem. 279(14), 13659-13667 (2004)
106. H. Nakayama: RecQ family helicases: roles as tumor suppressor proteins. Oncogene 21(58), 9008-9021 (2002)
107. C. Z. Bachrati and I. D. Hickson: RecQ helicases: suppressors of tumorigenesis and premature aging. Biochem. J. 374(Part 3), 577-606 (2003)
108. R. R. Khakkar, J. A. Cobb, L. Bjergbaek, I. D. Hickson and S. M Gasser: RecQ helicases: multiple roles in genome maintenance. Trends Cell Biol. 13(9), 493-501 (2003)
109. R. J. Bennett and J. L. Keck: Structure and function of RecQ DNA helicases. Crit. Rev. Biochem. Mol. Biol. 39(2), 79-97 (2004)
110. P. R. Prince, M. J. Emond and R. J. Monnat, Jr.: Loss of Werner syndrome protein function promotes aberrant recombination. Genes Dev. 15(8), 933-938 (2001)
111. N. Zhang, R. Kaur, X. Lu, X. Shen, L. Li and R. J. Legerski: The PSO4 mRNA splicing and DNA repair complex interacts with WRN for processing of DNA interstrand cross-links. J. Biol. Chem. 280(49), 40559-40567 (2005)
112. H. Yan, J. McCane, T. Toczylowski and C. Chen: Analysis of the Xenopus Werner syndrome protein in DNA double-strand break repair. J. Cell Biol. 171(2), 217-227 (2005)
113. J. E. Haber: DNA recombination: the replication connection. Trends Biochem. Sci. 24(7), 271-275 (1999)
114. S. C. Kowalczykowski: Initiation of genetic recombination and recombination-dependent replication. Trends Biochem. Sci. 25(4), 156-165 (2000)
115. B. Michel: Replication fork arrest and DNA recombination. Trends Biochem. Sci. 25(4), 173-178 (2000)
116. M. M. Cox: The non-mutagenic repair of broken replication forks via recombination. Mutat. Res. 510(1-2), 107-120 (2002)
117. P. McGlynn and R. G. Lloyd: Recombinational repair and restart of damaged replication forks. Nat. Rev. Mol. Cell Biol. 3(11), 859-870 (2002)
118. L. Hayflick and P. S. Moorhead: The serial cultivation of human diploid cell strains. Exp. Cell Res. 25, 585-621 (1961)
119. J. R. Smith and O. M. Pereira-Smith: Replicative senescence: implications for in vivo aging and tumor suppression. Science 273(5271), 63-67 (1996)
120. J. Campisi: Replicative senescence: an old lives' tale? Cell 84, 497-500 (1996)
121. R. G. A. Faragher and D. Kipling: How might replicative senescence contribute to human ageing? Bioessays 20(12), 985-991 (1998)
122. G. M. Martin, C. A. Sprague and C. J. Epstein: Replicative life-span of cultivated human cells: effects of donor's age, tissue, and genotype. Lab. Invest. 23(1), 86-92 (1970)
123. A. Machwe, D. K. Orren and V. A. Bohr: Accelerated methylation of ribosomal RNA genes during the cellular senescence of Werner syndrome fibroblasts. FASEB J. 14(12), 1715-1724 (2000)
124. J. Oshima, J. Campisi, T. C. A. Tannock and G. M. Martin: Regulation of c-fos expression in senescing Werner syndrome fibroblasts differs from that observed in senescing fibroblasts from normal donors. J. Cell Physiol. 162(2), 277-283 (1995)
125. T. Davis, S. K. Singhrao, F. S. Wyllie, M. F. Haughton, P. J. Smith, M. Wiltshire, D. Wynford-Thomas, C. J. Jones, R. G. A. Faragher and D. Kipling: Telomere-based proliferative lifespan barriers in Werner syndrome fibroblasts involve both p53-dependent and p53-independent mechanisms. J. Cell Sci. 116(Part 7), 1349-1357 (2003)
126. F. S. Wyllie, C. J. Jones, J. W. Skinner, M. F. Haughton, C. Wallis, D. Wynford-Thomas, R. G. A. Faragher and D. Kipling: Telomerase prevents the accelerated cell ageing of Werner syndrome fibroblasts. Nat. Genet. 24(1), 16-17 (2000)
127. D. Choi, P. S. Whittier, J. Oshima and W. D. Funk: Telomerase expression prevents replicative senescence but does not fully reset mRNA expression patterns in Werner syndrome cell strains. FASEB J. 15(6), 1014-1020 (2001)
128. M. M. Ouelette, L. D. McDaniel, W. E. Wright, J. W. Shay and R. A. Schultz: The establishment of telomerase-immortalized cell lines representing human chromosomal instability syndromes. Hum. Mol. Genet. 9(3), 403-411 (2000)
129. D. M. Baird, T. Davis, J. Rowson, C. J. Jones and D. Kipling: Normal telomere erosion rates at the single cell level in Werner syndrome fibroblast cells. Hum. Mol. Genet. 13(14), 1515-1524 (2004)
130. J. Karlseder, D. Broccoli, Y. Dai, S. Hardy and T. de Lange: p53- and ATM-dependent apoptosis induced by telomeres lacking TRF2. Science 283(5406), 132101325 (1999)
131. J. Karlseder, A. Smogorzewska and T. de Lange. Senescence caused by altered telomeric state, not telomere loss. Science 295(5564), 2446-2449 (2002)
132. R. C. Allsopp, H. Vaziri, C. Patterson, S. Goldstein, E. V. Younglai, A. B. Futcher, C. W. Greider and C. B. Harley: Telomere length predicts the replicative capacity of human fibroblasts. Proc. Natl. Acad. Sci. USA 89(21), 10114-10118 (1992)
133. V. P. Schulz, V. A. Zakian, C. E. Ogburn, J. McKay, A. A. Jarzebowicz, S. D. Edland and G. M. Martin: Accelerated loss of telomeric repeats may not explain accelerated replicative decline of Werner syndrome cells. Hum. Genet. 97(6), 750-754 (1996)
134. H. Tahara, Y. Tokutake, S. Maeda, H. Kataoka, T. Watanabe, M. Satoh, T. Matsumoto, M. Sugawara, T. Ide, M. Goto, Y. Furuichi and M. Sugimoto: Abnormal telomere dynamics of B-lymphoblastoid cell strains from Werner's syndrome patients transformed by Epstein-Barr virus. Oncogene 15(16), 1911-1920 (1997)
135. D. B. Lombard, C. Beard, B. Johnson, R. A. Marciniak, J. Dausman, R. Bronson, J. E. Buhlmann, R. Lipman, R. Curry, A. Sharpe, R. Jaenisch and L. Guarente: Mutations in the WRN gene in mice accelerate mortality in a p53-null background. Mol. Cell. Biol. 20(9), 3286-3291 (2000)
136. L. Wang, C. E. Ogburn, C. B. Ware, W. C. Ladiges, H. Youssoufian, G. M. Martin and J. Oshima: Cellular Werner phenotypes in mice expressing a putative dominant-negative human WRN gene. Genetics 154(1), 357-362 (2000)
137. H. W. Lee, M. A. Blasco, G. J. Gottlieb, J. W. Horner, C. W. Greider and R. A. DePinho: Essential role of mouse telomerase in highly proliferative organs. Nature 392(6676), 569-574 (1998)
138. S. Chang, A. S. Multani, N. G. Cabrera, M. L. Naylor, P. Laud, D. Lombard, S. Pathak, L. Guarente and R. A. DePinho: Essential role of limiting telomeres in the pathogenesis of Werner syndrome. Nat. Genet. 36(8), 877-882 (2004)
139. X. Du, J. Shen, N. Kugan, E. E. Furth, D. B. Lombard, C. Cheung, S. Pak, G. Luo, R. J. Pignolo, R. A. DePinho, L. Guarente and F. B. Johnson: Telomere shortening exposes functions for the mouse Werner and Bloom syndrome genes. Mol. Cell. Biol. 24(19), 8437-8446 (2004)
140. P. R. Laud, A. S. Multani, S. M. Bailey, L. Wu, J. Ma, C. Kingsley, M. Lebel, S. Pathak, R. A. DePinho and S. Chang: Elevated telomere-telomere recombination in WRN-deficient, telomere dysfunctional cells promotes escape from senescence and engagement of the ALT pathway. Genes Dev. 19(21), 2560-2570 (2005)
141. F. B. Johnson, R. A. Marciniak, M. McVey, S. A. Stewart, W. C. Hahn and L. Guarente: The Saccharomyces cerevisiae WRN homolog Sgs1p participates in telomere maintenance in cells lacking telomerase. EMBO J. 20(4), 905-913 (2001)
142. P. L. Opresko, M. Otterlei, J. Graakjaer, P. Bruheim, L. Dawut, S. Kolvraa, A. May, M. M. Seidman and V. A. Bohr: The Werner syndrome helicase and exonuclease cooperate to resolve telomeric D loops in a manner regulated by TRF1 and TRF2. Mol. Cell 14(6), 763-774 (2004)
143. L. Crabbe, R. E. Verdun, C. I. Haggblom and J. Karlseder: Defective telomere lagging strand synthesis in cells lacking WRN helicase activity. Science 306(5703), 1951-1953 (2004)
144. Y. Bai and J. P. Murnane: Telomere instability in a human tumor cell line expressing a dominant-negative WRN protein. Hum. Genet. 113(4), 337-347 (2003)
145. A. Muntoni and R. R. Reddel: The first molecular details of ALT in human tumor cells. Hum. Mol. Genet. 14(special no. 2), R191-R196 (2005)
146. T. Tsurimoto, A. Shinozaki, M. Yano, M. Seki and T. Enomoto: Human Werner helicase interacting protein 1 (WRNIP1) functions as a novel modulator for DNA polymerase delta. Genes Cells 10(1), 13-22 (2005)