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[Cancer Research 61, 1816-1819, March 1, 2001]
© 2001 American Association for Cancer Research

Advances in Brief

Tumorigenic Effect of Nonfunctional p53 or p21 in Mice Mutant in the Werner Syndrome Helicase1

Michel Lebel, Robert D. Cardiff and Philip Leder2

Centre de Recherche en Cancérologie de l’Université Laval. Pavillon Hôtel-Dieu de Québec, Quebec, Quebec G1R 2J6, Canada [M. L.]; Department of Pathology, The University of California, Davis, Center for Comparative Medicine, University of California, Davis, CA 95616 [R. D. C.]; and Department of Genetics, Howard Hughes Medical Institute, Harvard Medical School, Boston, MA 02115 [P. L.]


   ABSTRACT
Top
 ABSTRACT
Introduction
 Materials and Methods
 Results
 Discussion
 REFERENCES
 
Werner syndrome is an autosomal recessive disorder characterized by genomic instability and by the premature onset of a number of age-related diseases, including malignancy. To assess a potential collaboration between p21 or p53 cell cycle regulators and Wrn proteins, Wrn mutant mice were created and mated with p21 or p53 null mice to generate double mutants. The p21 null/Wrn mutant mice did not show an acceleration of tumorigenesis during the first year of life, suggesting that the p53-dependent G1-S cell cycle checkpoint (which operates via p21) is not involved in Wrn-abetted tumor suppression. In contrast, the p53 null/Wrn mutant mice were particularly remarkable with respect to the rapidity with which they developed tumors. These mice were also distinguished by the variety of tumors they developed compared to those that developed in p53 null mice. Such data suggest a genetic interaction between p53 and Wrn in which loss of Wrn provokes a more variable p53 response unrelated to its role in the G1-S cell cycle checkpoint.


   Introduction
Top
 ABSTRACT
 Introduction
Materials and Methods
 Results
 Discussion
 REFERENCES
 
Werner syndrome (WS)3 is a rare autosomal recessive disorder characterized by the premature onset of a number of processes associated with aging, including malignancy (1 , 2) . Lymphoid cells and cultured fibroblasts explanted from patients suffering from WS show several types of chromosomal rearrangements including deletions and variegated chromosomal translocations (3, 4, 5, 6) . These findings suggest that WS is a human genomic instability or mutator syndrome. The gene responsible for WS (WRN) was identified by positional cloning (7) . It codes for a protein containing seven helicase consensus domains that are identical to the Escherichia coli RecQ gene (8) and to the Sgs1 yeast helicase (9 , 10) . The protein also contains a 3'-5' exonuclease activity in addition to its 3'-5' helicase activity (11, 12, 13) . Recently, studies have demonstrated that the human WRN protein interacts with p53, which is a protein also important for genomic stability (14 , 15) .

The p53 protein is a transcription factor (16) whose level is increased in response to genotoxic stress such as DNA damage. This increase in p53 protein levels is thought to result in transcription of target genes that mediate many functions. Among its transcriptional targets is p21WAF1/CIP1 (17) , an inhibitor of cyclin-dependent kinase complexes (18) and also an inhibitor of proliferating cell nuclear antigen (PCNA) activity as well as DNA synthesis (19 , 20) . p53 function is required for G1 arrest (21) and it is believed that this arrest allows cells time to repair DNA damage before being fixed as mutations. The p21 protein is also involved in this cell cycle arrest (22) . It is induced by DNA damage and is found associated with inactive cyclin E/cyclin-dependent kinase 2 complexes which are essential for G1-S phase transition (23) .

In addition to cell cycle arrest, the ability of p53 to induce apoptosis is thought to be an important factor for its tumor suppressor function (24) . Thus, cells lacking p53 function continue to proliferate, perpetuating potentially oncogenic mutations. Indeed, >70% of p53-deficient mice develop tumors, especially lymphomas and sarcomas, by 6 months of age (25 , 26) .

We recently created a deletion of part of the helicase domain of the murine homologue of the WS gene in embryonic stem cells to study tumor development in mice (27) . These mutant mice were further crossed to p53 null (25) or p21 null mice (22) to assess genetically the effect of any G1 cell cycle checkpoint control defect on tumorigenesis. In what follows, we show that p53 null/Wrn{Delta}hel homozygous mutant mice show an acceleration of tumor formation as well as a change in the tumor spectrum compared to p53 null. In contrast, the p21 null/Wrn{Delta}hel homozygous mutant mice did not show an acceleration of tumorigenesis. These results suggest that alteration of a p53- and/or WRN-dependent pathway (possibly apoptotic) is more likely to be important in tumor progression than cell cycle checkpoint control in our mouse model.


   Materials and Methods
Top
 ABSTRACT
 Introduction
 Materials and Methods
Results
 Discussion
 REFERENCES
 
Wrn mice lacking part of the helicase domain were created by a homologous recombination strategy into embryonic stem cells as described previously (27) . Mice of all possible genotypes were generated by mating the chimeras with either Black Swiss or 129/SvEv mice and intercrossing the F1 and F2 generations. Animals were checked three times a week for any external mass, infection, bleeding, gasping, and overall decrease or change in activity or behavior. The date of such observation was recorded and animals were kept for an additional 2–4 weeks to assess any decline in the health status. If in each case the condition of the animal worsened, the mouse was sacrificed for histological examination of its organs as described previously (28) .


   Results
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results
Discussion
 REFERENCES
 
Like other members of the RecQ helicase superfamily, the mouse WS protein contains seven conserved helicase motifs and motifs III and IV are encoded by two separate exons as in the human gene homologue (29) . To assess in vivo the importance of the helicase domain, we designed a homologous recombination construct to replace a 4.1-kb genomic fragment containing these exons with a neo cassette in embryonic stem cells (27) . These embryonic stem cells were used to generate mutant mice. As described previously, a stable mutant protein is synthesized from the homozygous mutant mice, presumably, with a nonfunctional helicase domain. Therefore, these homozygous mice are referred as Wrn{Delta}hel/{Delta}hel mice. Fifty-four Wrn{Delta}hel/{Delta}hel mice were observed for a period of 1 year as described in "Materials and Methods." More than 90% of live-born Wrn{Delta}hel/{Delta}hel mice appeared normal during the first year of life. Ten percent of the mice died of an unknown cause or showed severe cardiac fibrosis upon dissection (data not shown). All 16 wild-type animals observed during the same period of time were healthy (data not shown). Several different tumors and other pathological findings were observed in homozygous mutant mice older than 15 months of age (Table 1)Citation . Approximately 62% of the mice had developed some type of hyperplasias or tumors in one of their organs by 24 months of age (Table 1Citation and data not shown). This is without considering the other symptoms that were or were not associated with cancer such as infections, inflammations, prolapses, fibrosis, and so forth (see Table 1Citation ). The examination of more wild-type mice of similar age are required to determine whether there is a significant difference in aging or tumorigenesis between both cohorts.


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  		Table 1 Phenotype of Wrn{Delta}hel/{Delta}hel mutant mice

 
To determine the effect of the p21 defect on tumorigenesis, Wrn mice were crossed to p21 null mice to generate p21 null/Wrn{Delta}hel/{Delta}hel mice. After 1 year of observation, only 10% of these mice (3 of 23 animals) looked ill. Upon dissection of these sick animals, severe cardiac fibrosis similar to that of the Wrn{Delta}hel/{Delta}hel mice was detected. Only, one p21 null/Wrn{Delta}hel/{Delta}hel mouse developed an hemangiosarcoma before the age of 12 months. Fifty-six percent of the p21 null/Wrn{Delta}hel/{Delta}hel mice older than 15 months of age had developed hyperplasias or tumors similar to those detected in Wrn{Delta}hel/{Delta}hel mice with the same latency (data not shown). Thus, there was no acceleration of tumorigenesis on this p21 null/Wrn{Delta}hel/{Delta}hel cohort compared to the Wrn{Delta}hel/{Delta}hel cohort.

To assess the joint role of p53 and Wrn in tumor progression, p53 null and Wrn{Delta}hel/{Delta}hel mice were crossed to generate p53 null/Wrn{Delta}hel/{Delta}hel animals. These were carefully followed up for over 6 months and scored for the occurrence of tumors. Fig. 1Citation shows that p53 null/Wrn{Delta}hel/{Delta}hel mice developed tumors more rapidly than p53 null mice. Half of the p53 null/Wrn{Delta}hel/{Delta}hel mutants had developed some type of illness or tumor by 3 months of age. Approximately 50% of the p53 null mice had developed a tumor by the age of 4–5 months. Histological analysis of the sick mice revealed that p53 null/Wrn{Delta}hel/{Delta}hel mutants developed a variety of unusual tumors compared to the p53 null or Wrn{Delta}hel/{Delta}hel mice in our colony (Table 2)Citation . Several sarcomas of the mouth, including the salivary glands, were noticed in the p53 null/Wrn{Delta}hel/{Delta}hel mice. Such tumors included rare pericytoma, spindle cell sarcoma, and chondrosarcoma. The p53 null mice mainly developed myeloid leukemias, hemangiosarcomas, thymomas, or malignant lymphomas (Table 2)Citation (25) . Several Wrn{Delta}hel/{Delta}hel mice also developed leukemias, thymomas, or lymphomas but none of them developed hemangiosarcomas (Table 1)Citation . These results indicate that deletion of the helicase domain of the Wrn protein affects tumor spectrum.



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  		Fig. 1. Percentage of symptom-free animals from Wrn{Delta}hel/{Delta}hel, p53 null, and p53 null/Wrn{Delta}hel/{Delta}hel mutant mice over a period of 8 months. Animals were checked three times a week for any external mass, infection, bleeding, gasping, and overall decrease or change in activity or behavior. The dates of such observations were recorded at the first appearance of a symptom in each mouse. Mice were kept for an additional 2 weeks to assess any decline in health status and for pathological examination. The number of animal (n) in this survey are indicated for each genotype.

 

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  		Table 2 Incidence of each phenotype in p53 null and p53 null/Wrn{Delta}hel/{Delta}helmutant mice

 
A number of p53 null/Wrn{Delta}hel/{Delta}hel mice (34%) developed several foci of hemangiosarcomas in different organs. In contrast, <11% of the p53 null mice had more than one focus of hemangiosarcoma. Moreover, 34% of the p53 null/Wrn{Delta}hel/{Delta}hel mutants simultaneously developed multiple types of tumors. Only 17% of Wrn{Delta}hel/{Delta}hel mice and none of the p53 null mice under survey developed multiple tumors (Tables 1Citation and 2Citation ). These observations indicate that p53 null/Wrn{Delta}hel/{Delta}hel mice rapidly develop aggressive tumors as well as unusual types of tumors compared to p53 null or Wrn{Delta}hel/{Delta}hel mice in our mixed genetic background (Black Swiss x 129/SvEv).


   Discussion
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
REFERENCES
 
The WS gene product contains both an exonuclease and a helicase domain. To assess the importance of the helicase domain, two exons coding for part of this domain were deleted by homologous recombination in mouse embryonic stem cells, leaving all other exons intact (27) . Further analysis with an antibody against the mouse Wrn protein indicated that a stable mutant protein was being synthesized in mutant mice. Although the smaller mutant contains an intact nuclear localization signal, it does not copurify with a protein complex containing PCNA and topoisomerase I (30) . This WRN/PCNA/topoisomerase I complex might be part of the bigger multiprotein DNA replication complex. Indeed, it has recently been shown that the human WRN protein interacts functionally with the DNA polymerase {delta} in yeast (31) .

The possibility that the Wrn{Delta}hel mutant protein has a dominant-negative effect cannot be ruled out at this point. However, it is interesting to note that heterozygous mutant embryonic stem cells are more sensitive to topoisomerase inhibitors than wild-type cells, but less sensitive than homozygous cells (27) . This intermediate sensitivity of heterozygous cells to a specific DNA-damaging agent parallels the findings that human heterozygous WRN mutant cells have an intermediate phenotype compared to homozygous and wild-type individuals in terms of sensitivity to a specific DNA-damaging agent and genomic instability (32 , 33) . It is, thus, possible that a deletion of part of the helicase domain might alter the three-dimensional structure of the helicase and its potential association with other cellular proteins that are part of a complex (30) . Our results suggest that the Wrn{Delta}hel mutant protein has no obvious dominant-negative activity. However, the Wrn protein may have other, as yet unknown, functions of which our mutation might affect only a subset.

The Wrn mutant mice with a p53-deficient background were remarkable with respect to the rapidity with which they developed tumors. Moreover, the p53 null/Wrn{Delta}hel/{Delta}hel mice were further remarkable by virtue of the variety of tumors to which they give rise as compared to p53 null or Wrn{Delta}hel/{Delta}hel mice. Leukemias, thymomas, and lymphomas were the only tumor types common to all three cohorts of mice. In addition, several p53 null/Wrn{Delta}hel/{Delta}hel mice rapidly and simultaneously developed multiple tumor types (Table 1)Citation , indicating a synergistic effect of the Wrn and p53 mutations in accord with previous findings with a Wrn null mutation (34) . These data also indicate that a simple deletion of the helicase domain of the Wrn protein is sufficient to induce accelerated tumorigenesis on a p53 null background.

The p53-Wrn genetic interaction might be accounted for by suggesting that the p53 defect allows cells to escape apoptosis which would be the normal consequence of DNA damage. Lesions in the DNA may cause the DNA replication fork to stall or to create breaks in the DNA. The Wrn protein, like RecQ in E. coli, may be required for ensuring that structural abnormalities arising during recombinational repair at the replication fork are corrected at a high level of fidelity (35) . Deletion of the helicase domain in the Wrn protein would increase genomic instability in already unstable p53 null-proliferating or precancerous cells in certain tissues. This increase in genomic instability would give rise to additional mutations accelerating tumor progression and aggressive behavior on a Wrn{Delta}hel/{Delta}hel mutant background. Interestingly, it has been shown recently that human WS cells have an attenuation of the p53-dependent apoptotic pathway (14) . A similar behavior in mice would certainly promote tumorigenesis.

In summary, p53 protein is an important component of cell cycle checkpoints. At least a portion of this p53-dependent cell cycle control is manifest via p21 induction which is, in turn, responsible for the G1-S cell cycle checkpoint. The fact that p21 null/Wrn{Delta}hel/{Delta}hel mice do not undergo accelerated tumorigenesis suggests that the G1-S checkpoint is not a focus of p53-dependent tumor suppression. More likely, the key suppressor pathway in our mouse model is via the induction of apoptosis which is also dependent on p53.


   ACKNOWLEDGMENTS
 
We are grateful to K. R. Fontaine for technical assistance and to J. E. Walls for her technical assistance with the histopathology.


   FOOTNOTES
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 M. L. is a recipient of a Research Fellowship of the National Cancer Institute of Canada supported with funds provided by the Terry Fox Run. Back

2 To whom requests for reprints should be addressed, at Department of Genetics, Howard Hughes Medical Institute, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115, Phone: (617) 432-7667; Fax: (617) 432-7663. Back

3 The abbreviations used are: WS, Werner syndrome; PCNA, proliferating cell nuclear antigen. Back

Received 9/27/00. Accepted 1/18/01.


   REFERENCES
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
 REFERENCES
 

  1. Epstein C. J., Martin G. M., Schultz A. L., Motulsky A. G. Werner’s syndrome: a review of its symptomatology, natural history, pathologic features, genetics and relationship to the natural aging process. Medicine, 45: 177-222, 1966.[Medline]
  2. Sato K., Goto M., Nishioka K., Arimu K., Hori N., Yamashita N., Fujimoto Y., Nanko H., Ohara K. Werner’s syndrome associated with malignancies: five case reports with a survey of case histories in Japan. Gerontology, 34: 212-218, 1988.[Medline]
  3. Scappaticci S, Cerimele D., Fraccaro M. Clonal structural chromosomal rearrangements in primary fibroblast cultures and in lymphocytes of patients with Werner’s Syndrome. Hum. Genet., 62: 16-24, 1982.[Medline]
  4. Maraschio P., Peretti D., Lambiase S., Lo Curto F., Caufin D., Gargantini L., Minoli L., Zuffardi O. A new chromosome instability disorder. Clin. Genet., 30: 353-365, 1986.[Medline]
  5. Fukuchi K., Tanaka K., Kumahara Y., Marumo K., Pride M. B., Martin G. M., Monnat R. J., Jr. Increased frequency of 6-thioguanine-resistant peripheral blood lymphocytes in Werner syndrome patients. Hum. Genet., 84: 249-252, 1990.[Medline]
  6. Melaragno M. I., Pagni D., Smith M. A. Cytogenetic aspects of Werner’s syndrome lymphocyte cultures. Mech. Ageing Dev., 78: 117-122, 1995.[Medline]
  7. Yu C-E., Oshima J., Fu Y-H., Wijsman E. M., Hisama F., Alish R., Matthews S., Nakura J., Miki T., Quais S., Martin G. M., Mulligan J., Schellenberg G. D. Positional cloning of the Werner’s syndrome gene. Science (Washington DC), 272: 258-262, 1996.[Abstract]
  8. Umezu K., Nakayama K., Nakayama H. Escherichia coli RecQ protein is a DNA helicase. Proc. Natl. Acad. Sci. USA, 87: 5363-5367, 1990.[Abstract/Free Full Text]
  9. Gangloff S., McDonald J. P., Bendixen C., Arthur L., Rothstein R. The yeast type I topoisomerase Top3 interacts with Sgs1, a DNA helicase homologue: a potential eukaryotic reverse gyrase. Mol. Cell. Biol., 14: 8391-8398, 1994.[Abstract/Free Full Text]
  10. Watt P. M., Louis E. J., Borts R. H., Hickson I. D. Sgs1: a eukaryotic homolog of E. coli RecQ that interacts with topoisomerase II in vivo and is required for faithful chromosome segregation. Cell, 81: 253-260, 1995.[Medline]
  11. Huang S., Li B., Gray M. D., Oshima J., Mian I. S., Campisi J. The premature ageing syndrome protein, WRN, is a 3' -> 5' exonuclease. Nat. Genet., 20: 114-116, 1998.[Medline]
  12. Kamath-Loeb A. S., Shen J. C., Loeb L. A., Fry M. Werner syndrome protein. II. Characterization of the integral 3' -> 5' DNA exonuclease. J. Biol. Chem., 273: 34145-34150, 1998.[Abstract/Free Full Text]
  13. Shen J. C., Gray M. D., Oshima J., Kamath-Loeb A. S., Fry M., Loeb L. A. Werner syndrome protein. I. DNA helicase and DNA exonuclease reside on the same polypeptide. J. Biol. Chem., 273: 34139-34144, 1998.[Abstract/Free Full Text]
  14. Blander G., Kipnis J., Leal J. F., Yu C. E., Schellenberg G. D., Oren M. Physical and functional interaction between p53 and the Werner’s syndrome protein. J. Biol. Chem., 274: 29463-29469, 1999.[Abstract/Free Full Text]
  15. Spillare E. A., Robles A. I., Wang X. W., Shen J. C., Yu C. E., Schellenberg G. D., Harris C. C. p53-mediated apoptosis is attenuated in Werner syndrome cells. Genes Dev., 13: 1355-1356, 1999.[Abstract/Free Full Text]
  16. Hinds P. W., Weinberg R. A. Tumor suppressor genes. Curr. Opin. Genet. Dev., 4: 135-141, 1994.[Medline]
  17. El-Deiry W. S., Tokino T., Velculescu V. E., Levy D. B., Parsons R., Trent J. M., Lin D., Mercer W. E., Kinzler K. W., Vogelstein B. WAF1, a potential mediator of p53 tumor suppression. Cell, 75: 817-825, 1993.[Medline]
  18. Harper J. W., Adami G. R., Wei N., Keyomarsi K., Elledge S. J. The p21 Cdk-interacting protein Cip1 is a potent inhibitor of G1 cyclin-dependent kinases. Cell, 75: 805-816, 1993.[Medline]
  19. Waga S., Hannon G. J., Beach D., Stillman B. The p21 inhibitor of cyclin-dependent kinases controls DNA replication by interaction with PCNA. Nature (Lond.), 369: 574-578, 1994.[Medline]
  20. Noda A., Ning Y., Venable S. F., Pereira-Smith O. M., Smith J. R. Cloning of senescent cell-derived inhibitors of DNA synthesis using an expression screen. Exp. Cell Res., 211: 90-98, 1994.[Medline]
  21. Kuerbitz S. J., Plunkett B. S., Walsh W. V., Kastan M. B. Wild-type p53 is a cell cycle checkpoint determinant following irradiation. Proc. Natl. Acad. Sci. USA, 89: 7491-7495, 1992.[Abstract/Free Full Text]
  22. Deng C., Zhang P., Harper J. W., Elledge S. J., Leder P. Mice lacking p21CIP1/WAF1 undergo normal development, but are defective in G1 checkpoint control. Cell, 82: 675-684, 1995.[Medline]
  23. Ohtsubo M., Theodoras A. M., Schumacher J., Roberts J. M., Pagano M. Human cyclin E, a nuclear protein essential for the G1-to-S phase transition. Mol. Cell. Biol., 15: 2612-2624, 1995.[Abstract]
  24. Levine A. J. p53, the cellular gatekeeper for growth and division. Cell, 88: 323-331, 1997.[Medline]
  25. Donehower L. A., Harvey M., Slagle B. L., McArthur M. J., Montgomery C. A., Jr., Butel J. S., Bradley A. Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours. Nature (Lond.), 356: 215-221, 1992.[Medline]
  26. Jacks T., Remington L., Williams B. O., Schmitt E. M., Halachmi S., Bronson R. T., Weinberg R. A. Tumor spectrum analysis in p53-mutant mice. Curr. Biol., 4: 1-7, 1994.[Medline]
  27. Lebel M., Leder P. 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: 13097-13102, 1998.[Abstract/Free Full Text]
  28. Elson A., Deng C., Campos-Torres J., Donehower L. A., Leder P. The MMTV/c-myc transgene and p53 null alleles collaborate to induce T-cell lymphomas, but not mammary carcinomas in transgenic mice. Oncogene, 11: 181-190, 1995.[Medline]
  29. Yu C-E., Oshima J., Wijsman E. M., Nakura J., Miki T., Piussan C., Matthews S., Fu Y-H., Mulligan J., Martin G. M., Schellenberg G. D., the Werner’s Syndrome Collaborative Group. Mutations in the consensus helicase domains of the Werner Syndrome gene. Am. J. Hum. Genet., 60: 330-341, 1997.[Medline]
  30. Lebel M., Spillare E. A., Harris C. C., Leder P. The Werner syndrome gene product copurifies with the DNA replication complex and interacts with PCNA and topoisomerase I. J. Biol. Chem., 274: 37795-37799, 1999.[Abstract/Free Full Text]
  31. Kamath-Loeb A. S., Johansson E., Burgers P. M. J., Loeb L. A. Functional interaction between the Werner syndrome protein and DNA polymerase {delta}. Proc. Natl. Acad. Sci. USA, 97: 4603-4608, 2000.[Abstract/Free Full Text]
  32. Ogburn C. E., Oshima J., Poot M., Chen R., Hunt K. E., Gollahon K. A., Rabinovitch P. S., Martin G. M. An apoptosis-inducing gendotoxin differentiates heterozygotic carriers for Werner helicase mutations from wild-type and homozygous mutants. Hum. Genet., 101: 121-125, 1997.[Medline]
  33. Moser M. J., Bigbee W. L., Grant S. G., Emond M. J., Langlois R. G., Jensen R. H., Oshima J., Monnat R. J., Jr. Genetic instability and hematologic disease risk in Werner syndrome patients and heterozygotes. Cancer Res., 60: 2492-2496, 2000.[Abstract/Free Full Text]
  34. Lombard D. B., Beard C., Johnson B., Marciniak R. A., Dausman J., Bronson R., Buhlmann J. E., Lipman R., Curry R., Sharpe A, Jaenisch R., Guarente L. Mutations in the WRN gene in mice accelerate mortality in a p53-null background. Mol. Cell. Biol., 20: 3286-3291, 2000.[Abstract/Free Full Text]
  35. Chakraverty R. K., Hickson I. D. Defending genome integrity during DNA replication: a proposed role for RecQ family helicases. Bioessays, 21: 286-294, 1999.[Medline]



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