Inactivation of yeast Isw2 chromatin remodeling enzyme mimics longevity effect of calorie restriction via induction of genotoxic stress response

Cell Metab. 2014 Jun 3;19(6):952-66. doi: 10.1016/j.cmet.2014.04.004. Epub 2014 May 8.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphatases / antagonists & inhibitors*
  • Adenosine Triphosphatases / genetics
  • Animals
  • Caenorhabditis elegans / metabolism*
  • Caenorhabditis elegans Proteins / genetics
  • Caloric Restriction
  • Cellular Senescence / physiology*
  • Chromatin Assembly and Disassembly / physiology
  • DNA Damage
  • DNA Repair / physiology
  • Gene Expression Profiling
  • Gene Expression Regulation, Fungal
  • Gene Knockout Techniques
  • Longevity
  • Peroxidases / biosynthesis
  • Rad51 Recombinase / biosynthesis
  • Rad51 Recombinase / genetics
  • Saccharomyces cerevisiae / metabolism*
  • Saccharomyces cerevisiae Proteins / antagonists & inhibitors*
  • Saccharomyces cerevisiae Proteins / biosynthesis
  • Saccharomyces cerevisiae Proteins / genetics
  • Stress, Physiological
  • Transcription Factors / antagonists & inhibitors*
  • Transcription Factors / genetics


  • ATHP-2 protein, C elegans
  • Caenorhabditis elegans Proteins
  • ISWI protein
  • Saccharomyces cerevisiae Proteins
  • Transcription Factors
  • PRX1 protein, S cerevisiae
  • Peroxidases
  • Rad51 Recombinase
  • Adenosine Triphosphatases

Associated data

  • GEO/GSE53721