title: A Genome Scale Screen for Mutants with Delayed Exit from Mitosis: Ire1-Independent Induction of Autophagy Integrates ER Homeostasis into Mitotic Lifespan.
abstract: Proliferating eukaryotic cells undergo a finite number of cell divisions before irreversibly exiting mitosis. Yet pathways that normally limit the number of cell divisions remain poorly characterized. Here we describe a screen of a collection of 3762 single gene mutants in the yeast Saccharomyces cerevisiae, accounting for 2/3 of annotated yeast ORFs, to search for mutants that undergo an atypically high number of cell divisions. Many of the potential longevity genes map to cellular processes not previously implicated in mitotic senescence, suggesting that regulatory mechanisms governing mitotic exit may be broader than currently anticipated. We focused on an ER-Golgi gene cluster isolated in this screen to determine how these ubiquitous organelles integrate into mitotic longevity. We report that a chronic increase in ER protein load signals an expansion in the assembly of autophagosomes in an Ire1-independent manner, accelerates trafficking of high molecular weight protein aggregates from the cytoplasm to the vacuoles, and leads to a profound enhancement of daughter cell production. We demonstrate that this catabolic network is evolutionarily conserved, as it also extends reproductive lifespan in the nematode Caenorhabditis elegans. Our data provide evidence that catabolism of protein aggregates, a natural byproduct of high protein synthesis and turn over in dividing cells, is among the drivers of mitotic longevity in eukaryotes.
authors.affiliation: Department of Anatomy & Cell Biology, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.
authors.forename: Ata
authors.initials: A
authors.lastname: Ghavidel
authors.affiliation: Department of Biology, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.
authors.forename: Kunal
authors.initials: K
authors.lastname: Baxi
authors.affiliation: Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Ignatchenko
authors.affiliation: Department of Anatomy & Cell Biology, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.
authors.forename: Martin
authors.initials: M
authors.lastname: Prusinkiewicz
authors.affiliation: Department of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.
authors.forename: Terra G
authors.initials: TG
authors.lastname: Arnason
authors.affiliation: Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Thomas
authors.initials: T
authors.lastname: Kislinger
authors.affiliation: Department of Biology, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.
authors.forename: Carlos E
authors.initials: CE
authors.lastname: Carvalho
authors.affiliation: Department of Anatomy & Cell Biology, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.
authors.forename: Troy A A
authors.initials: TA
authors.lastname: Harkness
mesh_terms: D000818:Animals; D001343:Autophagy; D017173:Caenorhabditis elegans; D029742:Caenorhabditis elegans Proteins / Q000502:physiology*; D004721:Endoplasmic Reticulum / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress; D016681:Genome, Fungal; D049751:Genome, Helminth; D006706:Homeostasis; D008562:Membrane Glycoproteins / Q000502:physiology*; D008938:Mitosis; D066329:Protein Aggregates; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D012098:Reproduction; D012441:Saccharomyces cerevisiae; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000502:physiology*; D056811:Unfolded Protein Response; D033921:Vesicular Transport Proteins / Q000235:genetics
chemical_list: D029742:Caenorhabditis elegans Proteins; D008562:Membrane Glycoproteins; D066329:Protein Aggregates; C089137:RER1 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D033921:Vesicular Transport Proteins; C082863:IRE1 protein, S cerevisiae; D017346:Protein Serine-Threonine Kinases