Genetic cooperation between the Werner syndrome protein and poly(ADP-ribose) polymerase-1 in preventing chromatid breaks, complex chromosomal rearrangements, and cancer in mice.
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(Deltahel/Deltahel) mice) were crossed to PARP-1-null mice. Both Wrn(Deltahel/Deltahel) and PARP-1-null/Wrn(Deltahel/Deltahel) cohorts developed more neoplasms than wild-type animals. The tumor spectrum was the same between PARP-1-null/Wrn(Deltahel/Deltahel) mice and Wrn mutants. However, PARP-1-null/Wrn(Deltahel/Deltahel) mice developed neoplasms at a younger age. Mouse embryonic fibroblasts derived from such PARP-1-null/Wrn(Deltahel/Deltahel) mice stop dividing abruptly unlike Wrn(Deltahel/Deltahel) or PARP-1-null cells. PARP-1-null/Wrn(Deltahel/Deltahel) 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.
Lebel
Michel
M
Centre de Recherche en Cancérologie de l'Université Laval, Hôpital Hôtel-Dieu de Québec, Centre Hospitalier Universitaire de Quebéc (CHUQ), Québec, Canada. michel.lebel@crhdq.ulaval.ca
Lavoie
Josée
J
Gaudreault
Isabelle
I
Bronsard
Marc
M
Drouin
Régen
R
D000375:Aging / Q000235:genetics / Q000502:physiology*; D000818:Animals; D002842:Chromatids / Q000235:genetics*; D002869:Chromosome Aberrations; D004265:DNA Helicases / Q000172:deficiency / Q000235:genetics*; D017931:DNA Primers; D004195:Disease Models, Animal; D005090:Exodeoxyribonucleases; D005260:Female; D015321:Gene Rearrangement; D006801:Humans; D008677:Metaphase; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology / Q000517:prevention & control*; D011065:Poly(ADP-ribose) Polymerases / Q000172:deficiency / Q000235:genetics*; D053484:RecQ Helicases; D014898:Werner Syndrome / Q000235:genetics; D000071657:Werner Syndrome Helicase
D017931:DNA Primers; D011065:Poly(ADP-ribose) Polymerases; D005090:Exodeoxyribonucleases; D004265:DNA Helicases; D053484:RecQ Helicases; C098785:WRN protein, human; D000071657:Werner Syndrome Helicase