title: Inactivation of yeast Isw2 chromatin remodeling enzyme mimics longevity effect of calorie restriction via induction of genotoxic stress response.
abstract: ATP-dependent chromatin remodeling is involved in all DNA transactions and is linked to numerous human diseases. We explored functions of chromatin remodelers during cellular aging. Deletion of ISW2, or mutations inactivating the Isw2 enzyme complex, extends yeast replicative lifespan. This extension by ISW2 deletion is epistatic to the longevity effect of calorie restriction (CR), and this mechanism is distinct from suppression of TOR signaling by CR. Transcriptome analysis indicates that isw2Δ partially mimics an upregulated stress response in CR cells. In particular, isw2Δ cells show an increased response to genotoxic stresses, and the DNA repair enzyme Rad51 is important for isw2Δ-mediated longevity. We show that lifespan is also extended in C. elegans by reducing levels of athp-2, a putative ortholog of Itc1/ACF1, a critical subunit of the enzyme complex. Our findings demonstrate that the ISWI class of ATP-dependent chromatin remodeling complexes plays a conserved role during aging and in CR.
authors.affiliation: Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA 19104, USA; Epigenetics Program, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Weiwei
authors.initials: W
authors.lastname: Dang
authors.affiliation: Department of Pathology, University of Washington, Seattle, WA 98195, USA.
authors.forename: George L
authors.initials: GL
authors.lastname: Sutphin
authors.affiliation: Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA 19104, USA; Epigenetics Program, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Jean A
authors.initials: JA
authors.lastname: Dorsey
authors.affiliation: Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA 19104, USA; Epigenetics Program, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Gabriel L
authors.initials: GL
authors.lastname: Otte
authors.affiliation: Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA 19104, USA; Epigenetics Program, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Kajia
authors.initials: K
authors.lastname: Cao
authors.affiliation: Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA 19104, USA; Epigenetics Program, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Rocco M
authors.initials: RM
authors.lastname: Perry
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Wanat
authors.affiliation: The Wistar Institute, Philadelphia, PA 19104, USA.
authors.forename: Dimitra
authors.initials: D
authors.lastname: Saviolaki
authors.affiliation: Department of Pathology, University of Washington, Seattle, WA 98195, USA.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Murakami
authors.affiliation: Buck Institute for Research on Aging, Novato, CA 94945, USA.
authors.forename: Scott
authors.initials: S
authors.lastname: Tsuchiyama
authors.affiliation: Buck Institute for Research on Aging, Novato, CA 94945, USA.
authors.forename: Brett
authors.initials: B
authors.lastname: Robison
authors.affiliation: Department of Biology, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Brian D
authors.initials: BD
authors.lastname: Gregory
authors.affiliation: Department Molecular Cancer Research, University Medical Center Utrecht, 3584 CG Utrecht, The Netherlands.
authors.forename: Michiel
authors.initials: M
authors.lastname: Vermeulen
authors.affiliation: The Wistar Institute, Philadelphia, PA 19104, USA.
authors.forename: Ramin
authors.initials: R
authors.lastname: Shiekhattar
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: F Brad
authors.initials: FB
authors.lastname: Johnson
authors.affiliation: The Wistar Institute, Philadelphia, PA 19104, USA.
authors.forename: Brian K
authors.initials: BK
authors.lastname: Kennedy
authors.affiliation: Department of Pathology, University of Washington, Seattle, WA 98195, USA.
authors.forename: Matt
authors.initials: M
authors.lastname: Kaeberlein
authors.affiliation: Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA 19104, USA; Epigenetics Program, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: bergers@upenn.edu.
authors.forename: Shelley L
authors.initials: SL
authors.lastname: Berger
mesh_terms: D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors* / Q000235:genetics; D000818:Animals; D017173:Caenorhabditis elegans / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics; D031204:Caloric Restriction; D016922:Cellular Senescence / Q000502:physiology*; D042002:Chromatin Assembly and Disassembly / Q000502:physiology; D004249:DNA Damage; D004260:DNA Repair / Q000502:physiology; D020869:Gene Expression Profiling; D015966:Gene Expression Regulation, Fungal; D055786:Gene Knockout Techniques; D008136:Longevity; D010544:Peroxidases / Q000096:biosynthesis; D051135:Rad51 Recombinase / Q000096:biosynthesis / Q000235:genetics; D012441:Saccharomyces cerevisiae / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D013312:Stress, Physiological; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000235:genetics
chemical_list: C000598557:ATHP-2 protein, C elegans; D029742:Caenorhabditis elegans Proteins; C086468:ISWI protein; D029701:Saccharomyces cerevisiae Proteins; D014157:Transcription Factors; C410041:PRX1 protein, S cerevisiae; D010544:Peroxidases; D051135:Rad51 Recombinase; D000251:Adenosine Triphosphatases