title: Identification of the Target of the Retrograde Response that Mediates Replicative Lifespan Extension in Saccharomyces cerevisiae.
abstract: The retrograde response signals mitochondrial status to the nucleus, compensating for accumulating mitochondrial dysfunction during Saccharomyces cerevisiae aging and extending replicative lifespan. The histone acetylase Gcn5 is required for activation of nuclear genes and lifespan extension in the retrograde response. It is part of the transcriptional coactivators SAGA and SLIK, but it is not known which of these complexes is involved. Genetic manipulation showed that these complexes perform interchangeably in the retrograde response. These results, along with the finding that the histone deacetylase Sir2 was required for a robust retrograde response informed a bioinformatics screen that reduced to four the candidate genes causal for longevity of the 410 retrograde response target genes. Of the four, only deletion of PHO84 suppressed lifespan extension. Retrograde-response activation of PHO84 displayed some preference for SAGA. Increased PHO84 messenger RNA levels from a second copy of the gene in cells in which the retrograde response is not activated achieved >80% of the lifespan extension observed in the retrograde response. Our studies resolve questions involving the roles of SLIK and SAGA in the retrograde response, pointing to the cooperation of these complexes in gene activation. They also finally pinpoint the gene that is both necessary and sufficient to extend replicative lifespan in the retrograde response. The finding that this gene is PHO84 opens up a new set of questions about the mechanisms involved, as this gene is known to have pleiotropic effects.
authors.affiliation: Tulane Center for Aging and Department of Medicine, Tulane University Health Sciences Center, New Orleans, Louisiana 70112.
authors.forename: James C
authors.initials: JC
authors.lastname: Jiang
authors.affiliation: Tulane Center for Aging and Department of Medicine, Tulane University Health Sciences Center, New Orleans, Louisiana 70112.
authors.forename: Stefan W
authors.initials: SW
authors.lastname: Stumpferl
authors.affiliation: Tulane Center for Aging and Department of Medicine, Tulane University Health Sciences Center, New Orleans, Louisiana 70112.
authors.forename: Anurag
authors.initials: A
authors.lastname: Tiwari
authors.affiliation: Tulane Center for Aging and Department of Medicine, Tulane University Health Sciences Center, New Orleans, Louisiana 70112.
authors.forename: Qian
authors.initials: Q
authors.lastname: Qin
authors.affiliation: Tulane Center for Aging and Department of Medicine, Tulane University Health Sciences Center, New Orleans, Louisiana 70112.
authors.forename: José F
authors.initials: JF
authors.lastname: Rodriguez-Quiñones
authors.affiliation: Tulane Center for Aging and Department of Medicine, Tulane University Health Sciences Center, New Orleans, Louisiana 70112 sjazwins@tulane.edu.
authors.forename: S Michal
authors.initials: SM
authors.lastname: Jazwinski
mesh_terms: D004261:DNA Replication / Q000235:genetics; D015966:Gene Expression Regulation, Fungal; D058685:Genetic Pleiotropy; D051548:Histone Acetyltransferases / Q000235:genetics*; D008136:Longevity / Q000235:genetics*; D008928:Mitochondria / Q000235:genetics; D028081:Proton-Phosphate Symporters / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D012441:Saccharomyces cerevisiae / Q000235:genetics; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics*; D038281:Silent Information Regulator Proteins, Saccharomyces cerevisiae / Q000235:genetics*; D056565:Sirtuin 2 / Q000235:genetics*; D015534:Trans-Activators / Q000235:genetics; D000099224:p300-CBP-Associated Factor
chemical_list: D051548:Histone Acetyltransferases; D028081:Proton-Phosphate Symporters; D012333:RNA, Messenger; D029701:Saccharomyces cerevisiae Proteins; D038281:Silent Information Regulator Proteins, Saccharomyces cerevisiae; D056565:Sirtuin 2; D015534:Trans-Activators; C105495:PHO84 protein, S cerevisiae; C507785:SAGA complex, S cerevisiae; C501392:GCN5 protein, S cerevisiae; D000099224:p300-CBP-Associated Factor; C087778:SIR2 protein, S cerevisiae
keywords: Pho84; SAGA/SLIK; Sir2; mitochondria; transcriptional coactivation