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 p19(ARF) senescence regulator or its downstream target p53. However, upon acute DNA damage or oncogene expression, SIRT1-deficient cells show normal p19(ARF) 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 p19(ARF) as a downstream effector in this pathway.
authors.affiliation: Howard Hughes Medical Institute, Children's Hospital, CBR Institute for Biomedical Research, Department of Genetics, Harvard University Medical School, Boston, MA 02115, USA.
authors.forename: Katrin F
authors.initials: KF
authors.lastname: Chua
authors.forename: Raul
authors.initials: R
authors.lastname: Mostoslavsky
authors.forename: David B
authors.initials: DB
authors.lastname: Lombard
authors.forename: Wendy W
authors.initials: WW
authors.lastname: Pang
authors.forename: Shin'ichi
authors.initials: S
authors.lastname: Saito
authors.forename: Sonia
authors.initials: S
authors.lastname: Franco
authors.forename: Dhruv
authors.initials: D
authors.lastname: Kaushal
authors.forename: Hwei-Ling
authors.initials: HL
authors.lastname: Cheng
authors.forename: Miriam R
authors.initials: MR
authors.lastname: Fischer
authors.forename: Nicole
authors.initials: N
authors.lastname: Stokes
authors.forename: Michael M
authors.initials: MM
authors.lastname: Murphy
authors.forename: Ettore
authors.initials: E
authors.lastname: Appella
authors.forename: Frederick W
authors.initials: FW
authors.lastname: Alt
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D016922:Cellular Senescence / Q000187:drug effects; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004249:DNA Damage / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology; D005347:Fibroblasts; D011905:Genes, ras / Q000235:genetics; D006861:Hydrogen Peroxide / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D041681:NIH 3T3 Cells; D018384:Oxidative Stress / Q000187:drug effects; D016196:S Phase / Q000187:drug effects; D056564:Sirtuin 1; D037761:Sirtuins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D025803:Tumor Suppressor Protein p14ARF / Q000378:metabolism
chemical_list: C417743:Cdkn2a protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; D025803:Tumor Suppressor Protein p14ARF; D004317:Doxorubicin; D006861:Hydrogen Peroxide; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; D037761:Sirtuins