Mammalian SIRT1 limits replicative life span in response to chronic genotoxic stress.
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.
Chua
Katrin F
KF
Howard Hughes Medical Institute, Children's Hospital, CBR Institute for Biomedical Research, Department of Genetics, Harvard University Medical School, Boston, MA 02115, USA.
Mostoslavsky
Raul
R
Lombard
David B
DB
Pang
Wendy W
WW
Saito
Shin'ichi
S
Franco
Sonia
S
Kaushal
Dhruv
D
Cheng
Hwei-Ling
HL
Fischer
Miriam R
MR
Stokes
Nicole
N
Murphy
Michael M
MM
Appella
Ettore
E
Alt
Frederick W
FW
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
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