@article{cbfb2534aefe45b083e16451945af073,
title = "SIRT1 Redistribution on Chromatin Promotes Genomic Stability but Alters Gene Expression during Aging",
abstract = "Genomic instability and alterations in gene expression are hallmarks of eukaryotic aging. The yeast histone deacetylase Sir2 silences transcription and stabilizes repetitive DNA, but during aging or in response to a DNA break, the Sir complex relocalizes to sites of genomic instability, resulting in the desilencing of genes that cause sterility, a characteristic of yeast aging. Using embryonic stem cells, we show that mammalian Sir2, SIRT1, represses repetitive DNA and a functionally diverse set of genes across the mouse genome. In response to DNA damage, SIRT1 dissociates from these loci and relocalizes to DNA breaks to promote repair, resulting in transcriptional changes that parallel those in the aging mouse brain. Increased SIRT1 expression promotes survival in a mouse model of genomic instability and suppresses age-dependent transcriptional changes. Thus, DNA damage-induced redistribution of SIRT1 and other chromatin-modifying proteins may be a conserved mechanism of aging in eukaryotes.",
keywords = "DNA, HUMDISEASE, SIGNALING",
author = "Philipp Oberdoerffer and Shaday Michan and Michael McVay and Raul Mostoslavsky and James Vann and Park, \{Sang Kyu\} and Andrea Hartlerode and Judith Stegmuller and Angela Hafner and Patrick Loerch and Wright, \{Sarah M.\} and Mills, \{Kevin D.\} and Azad Bonni and Yankner, \{Bruce A.\} and Ralph Scully and Prolla, \{Tomas A.\} and Alt, \{Frederick W.\} and Sinclair, \{David A.\}",
note = "Funding Information: D.A.S. wishes to thank B. Stillman and C. Westphal for advice and scientific discussions. We are also grateful to K. Rajewsky, D. Reinberg, D. Lamming, L. Guarente, A. Vaquero, and M. Jasin for advice and reagents. We thank E. Vollmann, J. Campbell, and D. Zimmerman for technical assistance and R. Bronson for mouse necropsy. We are especially grateful to P. Glenn, M. Collins, and L. Ellison for their support of aging research. P.O. was supported by a fellowship from the National Space Biomedical Research Institute (grant PF00903), the Sinclair Lab by grants RO1GM068072 and R01AG19719 (National Institutes of Health [NIH]), and the Glenn Foundation for Medical Research. D.A.S. and F.W.A. are Ellison Medical Foundation Senior Scholars. R.M. is a V and Kimmel Foundation Scholar. A.B. supported by NIH grant NS047188; R.S. by GM 073894; and J.V., S.P., and T.A.P. by R01AG 020681. F.W.A. is an Investigator of the Howard Hughes Medical Institute. D.A.S. is a consultant to Shaklee, Genocea, and Sirtris (a GSK company developing sirtuin-based drugs) and an inventor on Harvard patents licensed to GSK. ",
year = "2008",
month = nov,
day = "28",
doi = "10.1016/j.cell.2008.10.025",
language = "English",
volume = "135",
pages = "907--918",
journal = "Cell",
issn = "0092-8674",
number = "5",
}