Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Science 10 December 2004:
Vol. 306. no. 5703, pp. 1951 - 1953
DOI: 10.1126/science.1103619
Prev | Table of Contents | Next

Reports

Defective Telomere Lagging Strand Synthesis in Cells Lacking WRN Helicase Activity

Laure Crabbe, Ramiro E. Verdun, Candy I. Haggblom, Jan Karlseder*

Cells from Werner syndrome patients are characterized by slow growth rates, premature senescence, accelerated telomere shortening rates, and genome instability. The syndrome is caused by the loss of the RecQ helicase WRN, but the underlying molecular mechanism is unclear. Here we report that cells lacking WRN exhibit deletion of telomeres from single sister chromatids. Only telomeres replicated by lagging strand synthesis were affected, and prevention of loss of individual telomeres was dependent on the helicase activity of WRN. Telomere loss could be counteracted by telomerase activity. We propose that WRN is necessary for efficient replication of G-rich telomeric DNA, preventing telomere dysfunction and consequent genomic instability.

The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.

* To whom correspondence should be addressed. E-mail: Karlseder{at}salk.edu

Read the Full Text


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
A Recombination Hot Spot in HIV-1 Contains Guanosine Runs That Can Form a G-quartet Structure and Promote Strand Transfer in Vitro.
W. Shen, L. Gao, M. Balakrishnan, and R. A. Bambara (2009)
J. Biol. Chem. 284, 33883-33893
   Abstract »    Full Text »    PDF »
Telomeric armor: the layers of end protection.
L. Oganesian and J. Karlseder (2009)
J. Cell Sci. 122, 4013-4025
   Abstract »    Full Text »    PDF »
Origin-dependent initiation of DNA replication within telomeric sequences.
I. Kurth and J. Gautier (2009)
Nucleic Acids Res.
   Abstract »    Full Text »    PDF »
Arginine Methylation Regulates Telomere Length and Stability.
T. R. H. Mitchell, K. Glenfield, K. Jeyanthan, and X.-D. Zhu (2009)
Mol. Cell. Biol. 29, 4918-4934
   Abstract »    Full Text »    PDF »
Stabilization of quadruplex DNA perturbs telomere replication leading to the activation of an ATR-dependent ATM signaling pathway.
A. Rizzo, E. Salvati, M. Porru, C. D'Angelo, M. F. Stevens, M. D'Incalci, C. Leonetti, E. Gilson, G. Zupi, and A. Biroccio (2009)
Nucleic Acids Res. 37, 5353-5364
   Abstract »    Full Text »    PDF »
Identification and Characterization of Nucleolin as a c-myc G-quadruplex-binding Protein.
V. Gonzalez, K. Guo, L. Hurley, and D. Sun (2009)
J. Biol. Chem. 284, 23622-23635
   Abstract »    Full Text »    PDF »
From the Cover: Ku86 represses lethal telomere deletion events in human somatic cells.
Y. Wang, G. Ghosh, and E. A. Hendrickson (2009)
PNAS 106, 12430-12435
   Abstract »    Full Text »    PDF »
MRE11 complex links RECQ5 helicase to sites of DNA damage.
L. Zheng, R. Kanagaraj, B. Mihaljevic, S. Schwendener, A. A. Sartori, B. Gerrits, I. Shevelev, and P. Janscak (2009)
Nucleic Acids Res. 37, 2645-2657
   Abstract »    Full Text »    PDF »
The effect of the TRF2 N-terminal and TRFH regions on telomeric G-quadruplex structures.
I. M. Pedroso, W. Hayward, and T. M. Fletcher (2009)
Nucleic Acids Res. 37, 1541-1554
   Abstract »    Full Text »    PDF »
Telomere Dysfunction and DNA-PKcs Deficiency: Characterization and Consequence.
E. S. Williams, R. Klingler, B. Ponnaiya, T. Hardt, E. Schrock, S. P. Lees-Miller, K. Meek, R. L. Ullrich, and S. M. Bailey (2009)
Cancer Res. 69, 2100-2107
   Abstract »    Full Text »    PDF »
Human Wrnip1 Is Localized in Replication Factories in a Ubiquitin-binding Zinc Finger-dependent Manner.
N. Crosetto, M. Bienko, R. G. Hibbert, T. Perica, C. Ambrogio, T. Kensche, K. Hofmann, T. K. Sixma, and I. Dikic (2008)
J. Biol. Chem. 283, 35173-35185
   Abstract »    Full Text »    PDF »
Sgs1 RecQ Helicase Inhibits Survival of Saccharomyces cerevisiae Cells Lacking Telomerase and Homologous Recombination.
J. Y. Lee, J. L. Mogen, A. Chavez, and F. B. Johnson (2008)
J. Biol. Chem. 283, 29847-29858
   Abstract »    Full Text »    PDF »
Hypomethylation of subtelomeric regions in ICF syndrome is associated with abnormally short telomeres and enhanced transcription from telomeric regions.
S. Yehezkel, Y. Segev, E. Viegas-Pequignot, K. Skorecki, and S. Selig (2008)
Hum. Mol. Genet. 17, 2776-2789
   Abstract »    Full Text »    PDF »
WRN Is Required for ATM Activation and the S-Phase Checkpoint in Response to Interstrand Cross-Link-Induced DNA Double-Strand Breaks.
W.-H. Cheng, D. Muftic, M. Muftuoglu, L. Dawut, C. Morris, T. Helleday, Y. Shiloh, and V. A. Bohr (2008)
Mol. Biol. Cell 19, 3923-3933
   Abstract »    Full Text »    PDF »
Mechanism and substrate specificity of telomeric protein POT1 stimulation of the Werner syndrome helicase.
G. Sowd, M. Lei, and P. L. Opresko (2008)
Nucleic Acids Res. 36, 4242-4256
   Abstract »    Full Text »    PDF »
Telomere maintenance and human bone marrow failure.
R. T. Calado and N. S. Young (2008)
Blood 111, 4446-4455
   Abstract »    Full Text »    PDF »
Telomeres and Aging.
G. Aubert and P. M. Lansdorp (2008)
Physiol Rev 88, 557-579
   Abstract »    Full Text »    PDF »
WRN Controls Formation of Extrachromosomal Telomeric Circles and Is Required for TRF2{Delta}B-Mediated Telomere Shortening.
B. Li, S. P. Jog, S. Reddy, and L. Comai (2008)
Mol. Cell. Biol. 28, 1892-1904
   Abstract »    Full Text »    PDF »
Werner syndrome helicase activity is essential in maintaining fragile site stability.
L. M. Pirzio, P. Pichierri, M. Bignami, and A. Franchitto (2008)
J. Cell Biol. 180, 305-314
   Abstract »    Full Text »    PDF »
Genomic distribution and functional analyses of potential G-quadruplex-forming sequences in Saccharomyces cerevisiae.
S. G. Hershman, Q. Chen, J. Y. Lee, M. L. Kozak, P. Yue, L.-S. Wang, and F. B. Johnson (2008)
Nucleic Acids Res. 36, 144-156
   Abstract »    Full Text »    PDF »
Human premature aging, DNA repair and RecQ helicases.
R. M. Brosh Jr and V. A. Bohr (2007)
Nucleic Acids Res. 35, 7527-7544
   Abstract »    Full Text »    PDF »
Telomerase repeat addition processivity is increased at critically short telomeres in a Tel1-dependent manner in Saccharomyces cerevisiae.
M. Chang, M. Arneric, and J. Lingner (2007)
Genes & Dev. 21, 2485-2494
   Abstract »    Full Text »    PDF »
Physical and functional interactions between Werner syndrome helicase and mismatch-repair initiation factors.
N. Saydam, R. Kanagaraj, T. Dietschy, P. L. Garcia, J. Pena-Diaz, I. Shevelev, I. Stagljar, and P. Janscak (2007)
Nucleic Acids Res. 35, 5706-5716
   Abstract »    Full Text »    PDF »
Mechanisms of Cardiovascular Disease in Accelerated Aging Syndromes.
B. C. Capell, F. S. Collins, and E. G. Nabel (2007)
Circ. Res. 101, 13-26
   Abstract »    Full Text »    PDF »
Protection of DNA Ends by Telomeric 3' G-Tail Sequences.
Y.-C. Tsai, H. Qi, and L. F. Liu (2007)
J. Biol. Chem. 282, 18786-18792
   Abstract »    Full Text »    PDF »
Fission Yeast Taz1 and RPA Are Synergistically Required to Prevent Rapid Telomere Loss.
T. Kibe, Y. Ono, K. Sato, and M. Ueno (2007)
Mol. Biol. Cell 18, 2378-2387
   Abstract »    Full Text »    PDF »
The Werner Syndrome Helicase Is a Cofactor for HIV-1 Long Terminal Repeat Transactivation and Retroviral Replication.
A. Sharma, S. Awasthi, C. K. Harrod, E. F. Matlock, S. Khan, L. Xu, S. Chan, H. Yang, C. K. Thammavaram, R. A. Rasor, et al. (2007)
J. Biol. Chem. 282, 12048-12057
   Abstract »    Full Text »    PDF »
WRN at telomeres: implications for aging and cancer.
A. S. Multani and S. Chang (2007)
J. Cell Sci. 120, 713-721
   Abstract »    Full Text »    PDF »
Telomere dysfunction as a cause of genomic instability in Werner syndrome.
L. Crabbe, A. Jauch, C. M. Naeger, H. Holtgreve-Grez, and J. Karlseder (2007)
PNAS 104, 2205-2210
   Abstract »    Full Text »    PDF »
Telomestatin-induced Telomere Uncapping Is Modulated by POT1 through G-overhang Extension in HT1080 Human Tumor Cells.
D. Gomez, T. Wenner, B. Brassart, C. Douarre, M.-F. O'Donohue, V. El Khoury, K. Shin-ya, H. Morjani, C. Trentesaux, and J.-F. Riou (2006)
J. Biol. Chem. 281, 38721-38729
   Abstract »    Full Text »    PDF »
The Basic Domain of TRF2 Directs Binding to DNA Junctions Irrespective of the Presence of TTAGGG Repeats.
N. Fouche, A. J. Cesare, S. Willcox, S. Ozgur, S. A. Compton, and J. D. Griffith (2006)
J. Biol. Chem. 281, 37486-37495
   Abstract »    Full Text »    PDF »
Replication fork regression in repetitive DNAs.
N. Fouche, S. Ozgur, D. Roy, and J. D. Griffith (2006)
Nucleic Acids Res. 34, 6044-6050
   Abstract »    Full Text »    PDF »
A role for WRN in telomere-based DNA damage responses.
M. S. Eller, X. Liao, S. Liu, K. Hanna, H. Backvall, P. L. Opresko, V. A. Bohr, and B. A. Gilchrest (2006)
PNAS 103, 15073-15078
   Abstract »    Full Text »    PDF »
Human RECQ5{beta} helicase promotes strand exchange on synthetic DNA structures resembling a stalled replication fork.
R. Kanagaraj, N. Saydam, P. L. Garcia, L. Zheng, and P. Janscak (2006)
Nucleic Acids Res.
   Abstract »    Full Text »    PDF »
Gene function correlates with potential for G4 DNA formation in the human genome.
J. Eddy and N. Maizels (2006)
Nucleic Acids Res. 34, 3887-3896
   Abstract »    Full Text »    PDF »
Accumulation of FFA-1, the Xenopus Homolog of Werner Helicase, and DNA Polymerase {delta} on Chromatin in Response to Replication Fork Arrest.
N. Sasakawa, T. Fukui, and S. Waga (2006)
J. Biochem. 140, 95-103
   Abstract »    Full Text »    PDF »
WRN's Tenth Anniversary.
F. M. Hisama, V. A. Bohr, and J. Oshima (2006)
Sci. Aging Knowl. Environ. 2006, pe18
   Abstract »    Full Text »
The human Pif1 helicase, a potential Escherichia coli RecD homologue, inhibits telomerase activity.
D.-H. Zhang, B. Zhou, Y. Huang, L.-X. Xu, and J.-Q. Zhou (2006)
Nucleic Acids Res. 34, 1393-1404
   Abstract »    Full Text »    PDF »
Evidence that the S.cerevisiae Sgs1 protein facilitates recombinational repair of telomeres during senescence.
M. Azam, J. Y. Lee, V. Abraham, R. Chanoux, K. A. Schoenly, and F. B. Johnson (2006)
Nucleic Acids Res. 34, 506-516
   Abstract »    Full Text »    PDF »
Isolation of human Dna2 endonuclease and characterization of its enzymatic properties..
J.-H. Kim, H.-D. Kim, G.-H. Ryu, D.-H. Kim, J. Hurwitz, and Y.-S. Seo (2006)
Nucleic Acids Res. 34, 1854-1864
   Abstract »    Full Text »    PDF »
Telomeres, chromosome instability and cancer..
S. M. Bailey and J. P. Murnane (2006)
Nucleic Acids Res. 34, 2408-2417
   Abstract »    Full Text »    PDF »
Solution structure of a multifunctional DNA- and protein-binding motif of human Werner syndrome protein.
J.-S. Hu, H. Feng, W. Zeng, G.-x. Lin, and X. G. Xi (2005)
PNAS 102, 18379-18384
   Abstract »    Full Text »    PDF »
Modulation of Werner Syndrome Protein Function by a Single Mutation in the Conserved RecQ Domain.
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 (2005)
J. Biol. Chem. 280, 39627-39636
   Abstract »    Full Text »    PDF »
Elevated telomere-telomere recombination in WRN-deficient, telomere dysfunctional cells promotes escape from senescence and engagement of the ALT pathway.
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 (2005)
Genes & Dev. 19, 2560-2570
   Abstract »    Full Text »    PDF »
Analysis of the Xenopus Werner syndrome protein in DNA double-strand break repair.
H. Yan, J. McCane, T. Toczylowski, and C. Chen (2005)
J. Cell Biol. 171, 217-227
   Abstract »    Full Text »    PDF »
POT1 Stimulates RecQ Helicases WRN and BLM to Unwind Telomeric DNA Substrates.
P. L. Opresko, P. A. Mason, E. R. Podell, M. Lei, I. D. Hickson, T. R. Cech, and V. A. Bohr (2005)
J. Biol. Chem. 280, 32069-32080
   Abstract »    Full Text »    PDF »
Shelterin: the protein complex that shapes and safeguards human telomeres.
T. de Lange (2005)
Genes & Dev. 19, 2100-2110
   Abstract »    Full Text »    PDF »
Nuclear DNA Helicase II (RNA Helicase A) Interacts with Werner Syndrome Helicase and Stimulates Its Exonuclease Activity.
J. Friedemann, F. Grosse, and S. Zhang (2005)
J. Biol. Chem. 280, 31303-31313
   Abstract »    Full Text »    PDF »
Human POT1 disrupts telomeric G-quadruplexes allowing telomerase extension in vitro.
A. J. Zaug, E. R. Podell, and T. R. Cech (2005)
PNAS 102, 10864-10869
   Abstract »    Full Text »    PDF »
The Loss of a Single Telomere Can Result in Instability of Multiple Chromosomes in a Human Tumor Cell Line.
L. Sabatier, M. Ricoul, G. Pottier, and J. P. Murnane (2005)
Mol. Cancer Res. 3, 139-150
   Abstract »    Full Text »    PDF »


To Advertise     Find Products

Science. ISSN 0036-8075 (print), 1095-9203 (online)