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. Epub 2014 May 08

Weiwei Dang ¹ , George L Sutphin ² , Jean A Dorsey ¹ , Gabriel L Otte ¹ , Kajia Cao ¹ ,

Weiwei Dang ¹ , George L Sutphin ² , Jean A Dorsey ¹ , Gabriel L Otte ¹ , Kajia Cao ¹ , Rocco M Perry ¹ , Jennifer J Wanat ³ , Dimitra Saviolaki ⁴ , Christopher J Murakami ² , Scott Tsuchiyama ⁵ , Brett Robison ⁵ , Brian D Gregory ⁶ , Michiel Vermeulen ⁷ , Ramin Shiekhattar ⁴ , F Brad Johnson ³ , Brian K Kennedy ⁴ , Matt Kaeberlein ² , Shelley L Berger ⁸

+ et al

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.

摘要

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 isw2Î partially mimics an upregulated stress response in CR cells. In particular, isw2Î cells show an increased response to genotoxic stresses, and the DNA repair enzyme Rad51 is important for isw2Î-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.

基因

ISW2, athp-2

原始数据

保存测序数据

Sample name	Organism	Experiment title	Sample type	Library instrument	Attributes
Sample name	Organism	Experiment title	Sample type	Library instrument	biological replicate	growth protocol	source name	strain	treatment
ISW2K215R_CR	Saccharomyces cerevisiae	GSM1299404: ISW2K215R_CR; Saccharomyces cerevisiae; MNase-Seq	MNase-Seq	Illumina HiSeq 2000		Calorie-restricted	ISW2K215R Saccharomyces cerevisiae - calorie restricted	ISW2K215R	Mnase-treated DNA
ISW2K215R_NR	Saccharomyces cerevisiae	GSM1299403: ISW2K215R_NR; Saccharomyces cerevisiae; MNase-Seq	MNase-Seq	Illumina HiSeq 2000		Non-restricted	ISW2K215R Saccharomyces cerevisiae	ISW2K215R	Mnase-treated DNA
ISW2DEL_CR	Saccharomyces cerevisiae	GSM1299402: ISW2DEL_CR; Saccharomyces cerevisiae; MNase-Seq	MNase-Seq	Illumina HiSeq 2000		Calorie-restricted	ISW2DEL Saccharomyces cerevisiae - calorie restricted	ISW2DEL	Mnase-treated DNA
ISW2DEL_NR	Saccharomyces cerevisiae	GSM1299401: ISW2DEL_NR; Saccharomyces cerevisiae; MNase-Seq	MNase-Seq	Illumina HiSeq 2000		Non-restricted	ISW2DEL Saccharomyces cerevisiae	ISW2DEL	Mnase-treated DNA
WT_CR	Saccharomyces cerevisiae	GSM1299400: WT_CR; Saccharomyces cerevisiae; MNase-Seq	MNase-Seq	Illumina HiSeq 2000		Calorie-restricted	WT Saccharomyces cerevisiae - calorie restricted	WT	Mnase-treated DNA