Inactivation of Yeast Isw2 Chromatin Remodeling Enzyme Mimics Longevity Effect of Calorie Restriction via Induction of Genotoxic Stress Response

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. [Display omitted] •ISW2 deletion extends yeast replicative lifespan and is epistatic to CR•Isw2 regulates lifespan through stress response pathways•ISW2 deletion partially mimics CR effects on stress response pathways•Isw2-mediated longevity is TOR independent and likely conserved in eukaryotes Dang et al. show that the yeast chromatin remodeling complex Isw2 partially mimics the effects of calorie restriction and regulates lifespan through stress response pathways. This longevity regulation mechanism is independent of TOR signaling and may also be conserved in other eukaryotes.