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(American Journal of Pathology. 2003;162:1559-1569.)
© 2003 American Society for Investigative Pathology

Genetic Cooperation between the Werner Syndrome Protein and Poly(ADP-Ribose) Polymerase-1 in Preventing Chromatid Breaks, Complex Chromosomal Rearrangements, and Cancer in Mice

Michel Lebel*, Josée Lavoie{dagger}, Isabelle Gaudreault*, Marc Bronsard{dagger} and Régen Drouin{dagger}

From the Centre de Recherche en Cancérologie de l’Université Laval,* Hôpital Hôtel-Dieu de Québec, Centre Hospitalier Universitaire de Quebéc (CHUQ), Québec; and Unité de Recherche en Génétique Humaine et Moléculaire,{dagger} Hôpital Saint-François d’Assise, Centre Hospitalier Universitaire de Quebéc (CHUQ), Québec, Canada

Werner syndrome is a rare disorder characterized by the premature onset of a number of age-related diseases. The gene responsible for Werner syndrome encodes a DNA helicase/exonuclease protein. Participation in a replication complex is among the several functions postulated for the WRN protein. The poly(ADP-ribose) polymerase-1 (PARP-1) enzyme, which is known to bind to DNA strand breaks, is also associated with the DNA replication complex. To determine whether Wrn and PARP-1 enzymes act in concert during cell growth, mice with a mutation in the helicase domain of the Wrn gene (Wrn{Delta}hel/{Delta}hel mice) were crossed to PARP-1-null mice. Both Wrn{Delta}hel/{Delta}hel and PARP-1-null/Wrn{Delta}hel/{Delta}hel cohorts developed more neoplasms than wild-type animals. The tumor spectrum was the same between PARP-1-null/Wrn{Delta}hel/{Delta}hel mice and Wrn mutants. However, PARP-1-null/Wrn{Delta}hel/{Delta}hel mice developed neoplasms at a younger age. Mouse embryonic fibroblasts derived from such PARP-1-null/Wrn{Delta}hel/{Delta}hel mice stop dividing abruptly unlike Wrn{Delta}hel/{Delta}hel or PARP-1-null cells. PARP-1-null/Wrn{Delta}hel/{Delta}hel fibroblasts were distinguished by an increased frequency of chromatid breaks, complex chromosomal rearrangements, and fragmentation. Finally, experiments have indicated that the PARP-1 enzyme co-immunoprecipitates with the WRN protein in human 293 embryonic kidney cells. These results suggest that Wrn and PARP-1 enzymes may be part of a complex involved in the processing of DNA breaks.




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