@article{971b6c5b53684c91a7b0bb83b1afa966,
title = "Mammalian SIRT1 limits replicative life span in response to chronic genotoxic stress",
abstract = "The Saccharomyces cerevisiae chromatin silencing factor Sir2 suppresses genomic instability and extends replicative life span. In contrast, we find that mouse embryonic fibroblasts (MEFs) deficient for SIRT1, a mammalian Sir2 homolog, have dramatically increased resistance to replicative senescence. Extended replicative life span of SIRT1-deficient MEFs correlates with enhanced proliferative capacity under conditions of chronic, sublethal oxidative stress. In this context, SIRT1-deficient cells fail to normally upregulate either the p19ARF senescence regulator or its downstream target p53. However, upon acute DNA damage or oncogene expression, SIRT1-deficient cells show normal p19ARF induction and cell cycle arrest. Together, our findings demonstrate an unexpected SIRT1 function in promoting replicative senescence in response to chronic cellular stress and implicate p19ARF as a downstream effector in this pathway.",
author = "Chua, {Katrin F.} and Raul Mostoslavsky and Lombard, {David B.} and Pang, {Wendy W.} and Shin'ichi Saito and Sonia Franco and Dhruv Kaushal and Cheng, {Hwei Ling} and Fischer, {Miriam R.} and Nicole Stokes and Murphy, {Michael M.} and Ettore Appella and Alt, {Frederick W.}",
note = "Funding Information: We thank Ron Depinho, Charles Sherr, Jan-Hermen Dannenberg, Nabeel El-Bardeesy, Gregory David, William Hahn, Jayanta Chaudhuri, Or Gozani, and David Jung for helpful comments and reagents; Carl Barrett, Eriko Michishita, and Izumi Horikawa for helpful discussions and sharing unpublished observations; and Yuko Fujiwara, Aimee Williams, and Tiffany Borjeson from the Animal Core Facility. This work was supported by an Ellison Senior Scholar Award (to F.W.A), a Pfizer Post-doctoral Fellowship in Immunology/Rheumatology (to K.F.C.), a Long-Term Fellowship of the Human Frontier Science Program and a Senior Post-doctoral Fellowship from The Leukemia and Lymphoma Society (to R.M.), an NIA/NIH KO8 award (to D.B.L.), and a Long-Term Fellowship from the European Molecular Biology Organization (to S.F.). F.W.A. is an investigator and D.K. an associate of the Howard Hughes Medical Institute. ",
year = "2005",
month = jul,
doi = "10.1016/j.cmet.2005.06.007",
language = "English (US)",
volume = "2",
pages = "67--76",
journal = "Cell Metabolism",
issn = "1550-4131",
publisher = "Cell Press",
number = "1",
}