title: Fission yeast 26S proteasome mutants are multi-drug resistant due to stabilization of the Pap1 transcription factor.
abstract: Here we report the result of a genetic screen for mutants resistant to the microtubule poison methyl benzimidazol-2-yl carbamate (MBC) that were also temperature sensitive for growth. In total the isolated mutants were distributed in ten complementation groups. Cloning experiments revealed that most of the mutants were in essential genes encoding various 26S proteasome subunits. We found that the proteasome mutants are multi-drug resistant due to stabilization of the stress-activated transcription factor Pap1. We show that the ubiquitylation and ultimately the degradation of Pap1 depend on the Rhp6/Ubc2 E2 ubiquitin conjugating enzyme and the Ubr1 E3 ubiquitin-protein ligase. Accordingly, mutants lacking Rhp6 or Ubr1 display drug-resistant phenotypes.
authors.affiliation: Medical Research Council, Human Genetics Unit, Western General Hospital, Edinburgh, United Kingdom.
authors.forename: Mary
authors.initials: M
authors.lastname: Penney
authors.forename: Itaru
authors.initials: I
authors.lastname: Samejima
authors.forename: Caroline R
authors.initials: CR
authors.lastname: Wilkinson
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: McInerny
authors.forename: Søs G
authors.initials: SG
authors.lastname: Mathiassen
authors.forename: Mairi
authors.initials: M
authors.lastname: Wallace
authors.forename: Takashi
authors.initials: T
authors.lastname: Toda
authors.forename: Rasmus
authors.initials: R
authors.lastname: Hartmann-Petersen
authors.forename: Colin
authors.initials: C
authors.lastname: Gordon
mesh_terms: D020126:Brefeldin A / Q000494:pharmacology; D002110:Caffeine / Q000494:pharmacology; D018432:Drug Resistance, Multiple; D000073718:Pancreatitis-Associated Proteins; D046988:Proteasome Endopeptidase Complex / Q000235:genetics*; D012568:Schizosaccharomyces / Q000187:drug effects* / Q000235:genetics*; D029702:Schizosaccharomyces pombe Proteins / Q000235:genetics*; D019311:Staurosporine / Q000494:pharmacology; D054875:Ubiquitination
chemical_list: D000073718:Pancreatitis-Associated Proteins; C000612141:REG3A protein, human; D029702:Schizosaccharomyces pombe Proteins; D020126:Brefeldin A; D002110:Caffeine; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease; D019311:Staurosporine