title: A novel, evolutionarily conserved protein phosphatase complex involved in cisplatin sensitivity.
abstract: 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).
authors.affiliation: Institute for Systems Biology, Seattle, Washington 98103, USA. agingras@systemsbiology.org
authors.forename: Anne-Claude
authors.initials: AC
authors.lastname: Gingras
authors.forename: Michael
authors.initials: M
authors.lastname: Caballero
authors.forename: Marcel
authors.initials: M
authors.lastname: Zarske
authors.forename: Amy
authors.initials: A
authors.lastname: Sanchez
authors.forename: Tony R
authors.initials: TR
authors.lastname: Hazbun
authors.forename: Stanley
authors.initials: S
authors.lastname: Fields
authors.forename: Nahum
authors.initials: N
authors.lastname: Sonenberg
authors.forename: Ernst
authors.initials: E
authors.lastname: Hafen
authors.forename: Brian
authors.initials: B
authors.lastname: Raught
authors.forename: Ruedi
authors.initials: R
authors.lastname: Aebersold
mesh_terms: D002460:Cell Line; D002945:Cisplatin / Q000494:pharmacology*; D017124:Conserved Sequence; D004249:DNA Damage; D004342:Drug Hypersensitivity; D019143:Evolution, Molecular; D006801:Humans; D008954:Models, Biological; D046912:Multiprotein Complexes / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D010749:Phosphoprotein Phosphatases / Q000737:chemistry / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism*; D011485:Protein Binding; D012441:Saccharomyces cerevisiae / Q000166:cytology / Q000254:growth & development / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000032:analysis / Q000378:metabolism; D016415:Sequence Alignment; D020798:Two-Hybrid System Techniques
chemical_list: D046912:Multiprotein Complexes; D029701:Saccharomyces cerevisiae Proteins; D010749:Phosphoprotein Phosphatases; D002945:Cisplatin