This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Saintigny, Y.
Right arrow Articles by Monnat, R. J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Saintigny, Y.
Right arrow Articles by Monnat, R. J., Jr.

 Previous Article  |  Next Article 

Molecular and Cellular Biology, October 2002, p. 6971-6978, Vol. 22, No. 20
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.20.6971-6978.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Homologous Recombination Resolution Defect in Werner Syndrome

Yannick Saintigny,1,{dagger} Kate Makienko,1,{ddagger} Cristina Swanson,1 Mary J. Emond,2 and Raymond J. Monnat, Jr.1,3*

Departments of Pathology,1 Biostatistics,2 Genome Sciences, University of Washington, Seattle, Washington 98195-77053

Received 5 June 2002/ Returned for modification 5 July 2002/ Accepted 12 July 2002

Werner syndrome (WRN) is an uncommon autosomal recessive disease whose phenotype includes features of premature aging, genetic instability, and an elevated risk of cancer. We used three different experimental strategies to show that WRN cellular phenotypes of limited cell division potential, DNA damage hypersensitivity, and defective homologous recombination (HR) are interrelated. WRN cell survival and the generation of viable mitotic recombinant progeny could be rescued by expressing wild-type WRN protein or by expressing the bacterial resolvase protein RusA. The dependence of WRN cellular phenotypes on RAD51-dependent HR pathways was demonstrated by using a dominant-negative RAD51 protein to suppress mitotic recombination in WRN and control cells: the suppression of RAD51-dependent recombination led to significantly improved survival of WRN cells following DNA damage. These results define a physiological role for the WRN RecQ helicase protein in RAD51-dependent HR and identify a mechanistic link between defective recombination resolution and limited cell division potential, DNA damage hypersensitivity, and genetic instability in human somatic cells.

* Corresponding author. Mailing address: Departments of Pathology, Biostatistics, and Genome Sciences, University of Washington, Seattle, WA 98195-7705. Phone: (206) 616-7392. Fax: (206) 543-3967. E-mail: monnat{at}u.washington.edu.

{dagger} Present address: LMR-UMR CEA/CNRS 217, 92265 Fontenay aux Roses Cedex, France.

{ddagger} Present address: Dendreon Corporation, Seattle, WA 98121.

Molecular and Cellular Biology, October 2002, p. 6971-6978, Vol. 22, No. 20
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.20.6971-6978.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Zheng, L., Kanagaraj, R., Mihaljevic, B., Schwendener, S., Sartori, A. A., Gerrits, B., Shevelev, I., Janscak, P. (2009). MRE11 complex links RECQ5 helicase to sites of DNA damage. Nucleic Acids Res 37: 2645-2657 [Abstract] [Full Text]  
  • Ren, X., Lim, S., Smith, M. T., Zhang, L. (2009). Werner Syndrome Protein, WRN, Protects Cells from DNA Damage Induced by the Benzene Metabolite Hydroquinone. Toxicol Sci 107: 367-375 [Abstract] [Full Text]  
  • Franchitto, A., Pirzio, L. M., Prosperi, E., Sapora, O., Bignami, M., Pichierri, P. (2008). Replication fork stalling in WRN-deficient cells is overcome by prompt activation of a MUS81-dependent pathway. JCB 183: 241-252 [Abstract] [Full Text]  
  • Cheng, W.-H., Muftic, D., Muftuoglu, M., Dawut, L., Morris, C., Helleday, T., Shiloh, Y., Bohr, V. A. (2008). WRN Is Required for ATM Activation and the S-Phase Checkpoint in Response to Interstrand Cross-Link-Induced DNA Double-Strand Breaks. Mol. Biol. Cell 19: 3923-3933 [Abstract] [Full Text]  
  • Pirzio, L. M., Pichierri, P., Bignami, M., Franchitto, A. (2008). Werner syndrome helicase activity is essential in maintaining fragile site stability. JCB 180: 305-314 [Abstract] [Full Text]  
  • Saydam, N., Kanagaraj, R., Dietschy, T., Garcia, P. L., Pena-Diaz, J., Shevelev, I., Stagljar, I., Janscak, P. (2007). Physical and functional interactions between Werner syndrome helicase and mismatch-repair initiation factors. Nucleic Acids Res 35: 5706-5716 [Abstract] [Full Text]  
  • Machwe, A., Xiao, L., Lloyd, R. G., Bolt, E., Orren, D. K. (2007). Replication fork regression in vitro by the Werner syndrome protein (WRN): Holliday junction formation, the effect of leading arm structure and a potential role for WRN exonuclease activity. Nucleic Acids Res 35: 5729-5747 [Abstract] [Full Text]  
  • Das, A., Boldogh, I., Lee, J. W., Harrigan, J. A., Hegde, M. L., Piotrowski, J., de Souza Pinto, N., Ramos, W., Greenberg, M. M., Hazra, T. K., Mitra, S., Bohr, V. A. (2007). The Human Werner Syndrome Protein Stimulates Repair of Oxidative DNA Base Damage by the DNA Glycosylase NEIL1. J. Biol. Chem. 282: 26591-26602 [Abstract] [Full Text]  
  • Kamath-Loeb, A. S., Lan, L., Nakajima, S., Yasui, A., Loeb, L. A. (2007). Werner syndrome protein interacts functionally with translesion DNA polymerases. Proc. Natl. Acad. Sci. USA 104: 10394-10399 [Abstract] [Full Text]  
  • Ding, S.-l., Yu, J.-C., Chen, S.-T., Hsu, G.-C., Shen, C.-Y. (2007). Genetic Variation in the Premature Aging Gene WRN: A Case-Control Study on Breast Cancer Susceptibility. Cancer Epidemiol. Biomarkers Prev. 16: 263-269 [Abstract] [Full Text]  
  • Wagner, M., Price, G., Rothstein, R. (2006). The Absence of Top3 Reveals an Interaction Between the Sgs1 and Pif1 DNA Helicases in Saccharomyces cerevisiae. Genetics 174: 555-573 [Abstract] [Full Text]  
  • Hisama, F. M., Bohr, V. A., Oshima, J. (2006). WRN's Tenth Anniversary. Sci Aging Knowl Environ 2006: pe18-pe18 [Abstract] [Full Text]  
  • Choudhary, S., Doherty, K. M., Handy, C. J., Sayer, J. M., Yagi, H., Jerina, D. M., Brosh, R. M. Jr. (2006). Inhibition of Werner Syndrome Helicase Activity by Benzo[a]pyrene Diol Epoxide Adducts Can Be Overcome by Replication Protein A. J. Biol. Chem. 281: 6000-6009 [Abstract] [Full Text]  
  • Harrigan, J. A., Wilson, D. M. III, Prasad, R., Opresko, P. L., Beck, G., May, A., Wilson, S. H., Bohr, V. A. (2006). The Werner syndrome protein operates in base excision repair and cooperates with DNA polymerase {beta}. Nucleic Acids Res 34: 745-754 [Abstract] [Full Text]  
  • Bailey, S. M., Murnane, J. P. (2006). Telomeres, chromosome instability and cancer.. Nucleic Acids Res 34: 2408-2417 [Abstract] [Full Text]  
  • Zhang, N., Kaur, R., Lu, X., Shen, X., Li, L., Legerski, R. J. (2005). The Pso4 mRNA Splicing and DNA Repair Complex Interacts with WRN for Processing of DNA Interstrand Cross-links. J. Biol. Chem. 280: 40559-40567 [Abstract] [Full Text]  
  • Sharma, S., Sommers, J. A., Gary, R. K., Friedrich-Heineken, E., Hubscher, U., Brosh, R. M. Jr (2005). The interaction site of Flap Endonuclease-1 with WRN helicase suggests a coordination of WRN and PCNA. Nucleic Acids Res 33: 6769-6781 [Abstract] [Full Text]  
  • Doherty, K. M., Sharma, S., Uzdilla, L. A., Wilson, T. M., Cui, S., Vindigni, A., Brosh, R. M. Jr. (2005). RECQ1 Helicase Interacts with Human Mismatch Repair Factors That Regulate Genetic Recombination. J. Biol. Chem. 280: 28085-28094 [Abstract] [Full Text]  
  • Machwe, A., Xiao, L., Groden, J., Matson, S. W., Orren, D. K. (2005). RecQ Family Members Combine Strand Pairing and Unwinding Activities to Catalyze Strand Exchange. J. Biol. Chem. 280: 23397-23407 [Abstract] [Full Text]  
  • Ahn, B., Harrigan, J. A., Indig, F. E., Wilson, D. M. III, Bohr, V. A. (2004). Regulation of WRN Helicase Activity in Human Base Excision Repair. J. Biol. Chem. 279: 53465-53474 [Abstract] [Full Text]  
  • Sharma, S., Sommers, J. A., Brosh, R. M. Jr (2004). In vivo function of the conserved non-catalytic domain of Werner syndrome helicase in DNA replication. Hum Mol Genet 13: 2247-2261 [Abstract] [Full Text]  
  • Kovalchuk, O., Hendricks, C. A., Cassie, S., Engelward, A. J., Engelward, B. P. (2004). In vivo Recombination After Chronic Damage Exposure Falls to Below Spontaneous Levels in "Recombomice". Mol Cancer Res 2: 567-573 [Abstract] [Full Text]  
  • Choudhary, S., Sommers, J. A., Brosh, R. M. Jr. (2004). Biochemical and Kinetic Characterization of the DNA Helicase and Exonuclease Activities of Werner Syndrome Protein. J. Biol. Chem. 279: 34603-34613 [Abstract] [Full Text]  
  • Taylor, T. J., Knipe, D. M. (2004). Proteomics of Herpes Simplex Virus Replication Compartments: Association of Cellular DNA Replication, Repair, Recombination, and Chromatin Remodeling Proteins with ICP8. J. Virol. 78: 5856-5866 [Abstract] [Full Text]  
  • Seluanov, A., Mittelman, D., Pereira-Smith, O. M., Wilson, J. H., Gorbunova, V. (2004). DNA end joining becomes less efficient and more error-prone during cellular senescence. Proc. Natl. Acad. Sci. USA 101: 7624-7629 [Abstract] [Full Text]  
  • Cheng, W.-H., von Kobbe, C., Opresko, P. L., Arthur, L. M., Komatsu, K., Seidman, M. M., Carney, J. P., Bohr, V. A. (2004). Linkage between Werner Syndrome Protein and the Mre11 Complex via Nbs1. J. Biol. Chem. 279: 21169-21176 [Abstract] [Full Text]  
  • Opresko, P. L., Cheng, W.-H., Bohr, V. A. (2004). Junction of RecQ Helicase Biochemistry and Human Disease. J. Biol. Chem. 279: 18099-18102 [Full Text]  
  • Monnat, R. J. Jr., Saintigny, Y. (2004). Werner Syndrome Protein--Unwinding Function to Explain Disease. Sci Aging Knowl Environ 2004: re3-re3 [Abstract] [Full Text]  
  • Susse, S., Scholz, C.-J., Burkle, A., Wiesmuller, L. (2004). Poly(ADP-ribose) polymerase (PARP-1) and p53 independently function in regulating double-strand break repair in primate cells. Nucleic Acids Res 32: 669-680 [Abstract] [Full Text]  
  • Davies, S. L., North, P. S., Dart, A., Lakin, N. D., Hickson, I. D. (2004). Phosphorylation of the Bloom's Syndrome Helicase and Its Role in Recovery from S-Phase Arrest. Mol. Cell. Biol. 24: 1279-1291 [Abstract] [Full Text]  
  • Blais, V., Gao, H., Elwell, C. A., Boddy, M. N., Gaillard, P.-H. L., Russell, P., McGowan, C. H. (2004). RNA Interference Inhibition of Mus81 Reduces Mitotic Recombination in Human Cells. Mol. Biol. Cell 15: 552-562 [Abstract] [Full Text]  
  • Sharma, S., Otterlei, M., Sommers, J. A., Driscoll, H. C., Dianov, G. L., Kao, H.-I, Bambara, R. A., Brosh, R. M. Jr. (2004). WRN Helicase and FEN-1 Form a Complex upon Replication Arrest and Together Process Branchmigrating DNA Structures Associated with the Replication Fork. Mol. Biol. Cell 15: 734-750 [Abstract] [Full Text]  
  • McCulloch, S. D., Gu, L., Li, G.-M. (2003). Nick-dependent and -independent Processing of Large DNA Loops in Human Cells. J. Biol. Chem. 278: 50803-50809 [Abstract] [Full Text]  
  • Plchova, H., Hartung, F., Puchta, H. (2003). Biochemical Characterization of an Exonuclease from Arabidopsis thaliana Reveals Similarities to the DNA Exonuclease of the Human Werner Syndrome Protein. J. Biol. Chem. 278: 44128-44138 [Abstract] [Full Text]  
  • Laine, J.-P., Opresko, P. L., Indig, F. E., Harrigan, J. A., von Kobbe, C., Bohr, V. A. (2003). Werner Protein Stimulates Topoisomerase I DNA Relaxation Activity. Cancer Res. 63: 7136-7146 [Abstract] [Full Text]  
  • Driscoll, H. C., Matson, S. W., Sayer, J. M., Kroth, H., Jerina, D. M., Brosh, R. M. Jr. (2003). Inhibition of Werner Syndrome Helicase Activity by Benzo[c]phenanthrene Diol Epoxide dA Adducts in DNA Is Both Strand-and Stereoisomer-dependent. J. Biol. Chem. 278: 41126-41135 [Abstract] [Full Text]  
  • Baynton, K., Otterlei, M., Bjoras, M., von Kobbe, C., Bohr, V. A., Seeberg, E. (2003). WRN Interacts Physically and Functionally with the Recombination Mediator Protein RAD52. J. Biol. Chem. 278: 36476-36486 [Abstract] [Full Text]  
  • Cheng, W.-H., von Kobbe, C., Opresko, P. L., Fields, K. M., Ren, J., Kufe, D., Bohr, V. A. (2003). Werner Syndrome Protein Phosphorylation by Abl Tyrosine Kinase Regulates Its Activity and Distribution. Mol. Cell. Biol. 23: 6385-6395 [Abstract] [Full Text]  
  • Cheng, W.-H., Bohr, V. A. (2003). Diverse Dealings of the Werner Helicase/Nuclease. Sci Aging Knowl Environ 2003: pe22-22 [Abstract] [Full Text]  
  • Grandori, C., Wu, K.-J., Fernandez, P., Ngouenet, C., Grim, J., Clurman, B. E., Moser, M. J., Oshima, J., Russell, D. W., Swisshelm, K., Frank, S., Amati, B., Dalla-Favera, R., Monnat, R. J. Jr. (2003). Werner syndrome protein limits MYC-induced cellular senescence. Genes Dev. 17: 1569-1574 [Abstract] [Full Text]  
  • Sharma, S., Sommers, J. A., Driscoll, H. C., Uzdilla, L., Wilson, T. M., Brosh, R. M. Jr. (2003). 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. J. Biol. Chem. 278: 23487-23496 [Abstract] [Full Text]  
  • Harrigan, J. A., Opresko, P. L., von Kobbe, C., Kedar, P. S., Prasad, R., Wilson, S. H., Bohr, V. A. (2003). The Werner Syndrome Protein Stimulates DNA Polymerase {beta} Strand Displacement Synthesis via Its Helicase Activity. J. Biol. Chem. 278: 22686-22695 [Abstract] [Full Text]  
  • Hendricks, C. A., Almeida, K. H., Stitt, M. S., Jonnalagadda, V. S., Rugo, R. E., Kerrison, G. F., Engelward, B. P. (2003). Spontaneous mitotic homologous recombination at an enhanced yellow fluorescent protein (EYFP) cDNA direct repeat in transgenic mice. Proc. Natl. Acad. Sci. USA 100: 6325-6330 [Abstract] [Full Text]  
  • Linke, S. P., Sengupta, S., Khabie, N., Jeffries, B. A., Buchhop, S., Miska, S., Henning, W., Pedeux, R., Wang, X. W., Hofseth, L. J., Yang, Q., Garfield, S. H., Sturzbecher, H.-W., Harris, C. C. (2003). p53 Interacts with hRAD51 and hRAD54, and Directly Modulates Homologous Recombination. Cancer Res. 63: 2596-2605 [Abstract] [Full Text]  
  • Opresko, P. L., Cheng, W.-H., von Kobbe, C., Harrigan, J. A., Bohr, V. A. (2003). Werner syndrome and the function of the Werner protein; what they can teach us about the molecular aging process.. Carcinogenesis 24: 791-802 [Abstract] [Full Text]  
  • Fabre, F., Chan, A., Heyer, W.-D., Gangloff, S. (2002). Alternate pathways involving Sgs1/Top3, Mus81/ Mms4, and Srs2 prevent formation of toxic recombination intermediates from single-stranded gaps created by DNA replication. Proc. Natl. Acad. Sci. USA 99: 16887-16892 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»