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

Weiwei Dang, George L. Sutphin, Jean A. Dorsey, Gabriel L. Otte, Kajia Cao, Rocco M. Perry, Jennifer J. Wanat, Dimitra Saviolaki, Christopher J. Murakami, Scott Tsuchiyama, Brett Robison, Brian D. Gregory, Michiel Vermeulen, Ramin Shiekhattar, F. Brad Johnson, Brian K. Kennedy, Matt Kaeberlein, Shelley L. Berger

Research output: Contribution to journalArticle

46 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)952-966
Number of pages15
JournalCell Metabolism
Volume19
Issue number6
DOIs
StatePublished - Jun 3 2014

ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Cell Biology

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    Dang, W., Sutphin, G. L., Dorsey, J. A., Otte, G. L., Cao, K., Perry, R. M., Wanat, J. J., Saviolaki, D., Murakami, C. J., Tsuchiyama, S., Robison, B., Gregory, B. D., Vermeulen, M., Shiekhattar, R., Johnson, F. B., Kennedy, B. K., Kaeberlein, M., & Berger, S. L. (2014). Inactivation of yeast Isw2 chromatin remodeling enzyme mimics longevity effect of calorie restriction via induction of genotoxic stress response. Cell Metabolism, 19(6), 952-966. https://doi.org/10.1016/j.cmet.2014.04.004