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Human Molecular Genetics Advance Access published online on September 29, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi362
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© The Author 2005. Published by Oxford University Press. All rights reserved
Received August 8, 2005
Revised September 22, 2005
Accepted September 22, 2005

Article

In vivo misregulation of genes involved in apoptosis, development, and oxidative stress in mice lacking both functional Werner Syndrome protein and poly(ADP-ribose) polymerase-1

François Deschênes 1, Laurent Massip 1, Chantal Garand 1, and Michel Lebel 2*

1 Centre de Recherche en Cancérologie de l'Université Laval, Hôpital Hôtel-Dieu de Québec, Québec, Canada
2 Centre de Recherche en Cancérologie de l'Université Laval, Hôpital Hôtel-Dieu de Québec, 9 McMahon St, Québec, Québec G1R 2J6, Canada

* To whom correspondence should be addressed.
Michel Lebel, E-mail: michel.lebel{at}crhdq.ulaval.ca


  Abstract

Werner syndrome (WS) is a rare disorder characterized by the premature onset of a number of age-related diseases. The gene responsible for WS is believed to be involved in different aspects of transcription, replication, and/or DNA repair. The poly(ADP-ribose) polymerase-1 (PARP-1) enzyme is also involved in DNA repair and is known to affect transcription of several genes. In this study, we examined the expression profile of cells lacking the normal function of either or both enzymes. All mutant cells exhibited altered expression of genes normally responding to oxidative stress. Interestingly, more than 58% of misregulated genes identified in double mutant cells were not altered in cells with either the Wrn or PARP-1 mutation alone. Consequently, the impact on gene expression profile when both Wrn and PARP-1 are mutated was greater than a simple addition of individual mutant genotype. In addition, double mutant cultured cells showed major misregulation of genes involved in apoptosis, cell cycle control, embryonic development, metabolism, and signal transduction. More importantly, in vivo analyses of double mutant mice have confirmed the increased apoptosis and the developmental defects in embryos as well as the major increase in intracellular phosphorylation and oxidative DNA damage in adult tissues. They also exhibited a progressive increase in oxidative stress with age. Thus, a major result of this study is that changes in expression of several genes and physiological functions identified in vitro were confirmed in mouse embryonic and adult tissues.


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