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

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

Author information

1
Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA 19104, USA; Epigenetics Program, University of Pennsylvania, Philadelphia, PA 19104, USA.
2
Department of Pathology, University of Washington, Seattle, WA 98195, USA.
3
Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
4
The Wistar Institute, Philadelphia, PA 19104, USA.
5
Buck Institute for Research on Aging, Novato, CA 94945, USA.
6
Department of Biology, University of Pennsylvania, Philadelphia, PA 19104, USA.
7
Department Molecular Cancer Research, University Medical Center Utrecht, 3584 CG Utrecht, The Netherlands.
8
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.

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.

PMID:
24814484
PMCID:
PMC4106248
DOI:
10.1016/j.cmet.2014.04.004
[Indexed for MEDLINE]
Free PMC Article

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