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Molecular & Cellular Proteomics 4:1725-1740, 2005.
© 2005 by The American Society for Biochemistry and Molecular Biology, Inc.





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From the
Institute for Systems Biology, Seattle, Washington 98103, ¶ Zoological Institute and ¶¶ Faculty of Natural Science, University of Zurich, Zurich CH-8057, Switzerland, || Howard Hughes Medical Institute, Departments of Genome Sciences and Medicine, University of Washington, Seattle, Washington 98195, 
Department of Biochemistry and McGill Cancer Centre, McGill University, Montréal, Quebec H3G 1Y6, Canada, and 
Institute for Molecular Systems Biology, ETH Hönggerberg, Zurich CH-8093, Switzerland
Using a combination of tandem affinity purification tagging and mass spectrometry, we characterized a novel, evolutionarily conserved protein phosphatase 4 (PP4)-containing complex (PP4cs, protein phosphatase 4, cisplatin-sensitive complex) that plays a critical role in the eukaryotic DNA damage response. PP4cs is comprised of the catalytic subunit PP4C; a known regulatory subunit, PP4R2; and a novel protein that we termed PP4R3. The Saccharomyces cerevisiae PP4R3 ortholog Psy2 was identified previously in a screen for sensitivity to the DNA-damaging agent and anticancer drug cisplatin. We demonstrated that deletion of any of the PP4cs complex orthologs in S. cerevisiae elicited cisplatin hypersensitivity. Furthermore human PP4R3 complemented the yeast psy2 deletion, and Drosophila melanogaster lacking functional PP4R3 (flfl) exhibited cisplatin hypersensitivity, suggesting a highly conserved role for PP4cs in DNA damage repair. Finally we found that PP4R3 may target PP4cs to the DNA damage repair machinery at least in part via an interaction with Rad53 (CHK2).
Supported by a postdoctoral fellowship from the Canadian Institutes of Health Research. To whom correspondence should be addressed. Tel.: 206-732-1393; Fax: 206-732-1299; E-mail: agingras{at}systemsbiology.org
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