title: Genome-wide fitness and expression profiling implicate Mga2 in adaptation to hydrogen peroxide.
abstract: Caloric restriction extends lifespan, an effect once thought to involve attenuation of reactive oxygen species (ROS) generated by aerobic metabolism. However, recent evidence suggests that caloric restriction may in fact raise ROS levels, which in turn provides protection from acute doses of oxidant through a process called adaptation. To shed light on the molecular mechanisms of adaptation, we designed a series of genome-wide deletion fitness and mRNA expression screens to identify genes involved in adaptation to hydrogen peroxide. Combined with known transcriptional interactions, the integrated data implicate Yap1 and Skn7 as central transcription factors of both the adaptive and acute oxidative responses. They also identify the transcription factors Mga2 and Rox1 as active exclusively in the adaptive response and show that Mga2 is essential for adaptation. These findings are striking because Mga2 and Rox1 have been thought to control the response to hypoxic, not oxidative, conditions. Expression profiling of mga2Delta and rox1Delta knockouts shows that these factors most strongly regulate targets in ergosterol, fatty-acid, and zinc metabolic pathways. Direct quantitation of ergosterol reveals that its basal concentration indeed depends on Mga2, but that Mga2 is not required for the decrease in ergosterol observed during adaptation.
authors.affiliation: Program in Bioinformatics, University of California San Diego, La Jolla, California, USA.
authors.forename: Ryan
authors.initials: R
authors.lastname: Kelley
authors.forename: Trey
authors.initials: T
authors.lastname: Ideker
mesh_terms: D020869:Gene Expression Profiling; D023281:Genomics; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D008565:Membrane Proteins; D008957:Models, Genetic; D018384:Oxidative Stress; D012333:RNA, Messenger / Q000378:metabolism; D017382:Reactive Oxygen Species; D012097:Repressor Proteins / Q000235:genetics; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics* / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics
chemical_list: C542266:MGA2 protein, S cerevisiae; D008565:Membrane Proteins; D012333:RNA, Messenger; C083348:ROX1 protein, S cerevisiae; D017382:Reactive Oxygen Species; D012097:Repressor Proteins; C087570:SPT23 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D015534:Trans-Activators; D014157:Transcription Factors; C086677:YAP1 protein, S cerevisiae; D006861:Hydrogen Peroxide