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

SUMMARY ATP-dependent chromatin remodeling is involved in all DNA transactions and is linked to numerous human diseases.Weexploredfunctionsofchromatin remodelers during cellular aging.Deletion ofISW2,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 isw2D partially mimicsanupregulatedstressresponseinCRcells.In particular, isw2D cells show an increased response to genotoxic stresses, and the DNA repair enzyme Rad51 is important for isw2D-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.