哺乳动物的SIRT1在应对慢性基因毒性应激时会限制复制寿命。
Mammalian SIRT1 limits replicative life span in response to chronic genotoxic stress.
作者信息
Chua Katrin F, Mostoslavsky Raul, Lombard David B, Pang Wendy W, Saito Shin'ichi, Franco Sonia, Kaushal Dhruv, Cheng Hwei-Ling, Fischer Miriam R, Stokes Nicole, Murphy Michael M, Appella Ettore, Alt Frederick W
机构信息
Howard Hughes Medical Institute, Children's Hospital, CBR Institute for Biomedical Research, Department of Genetics, Harvard University Medical School, Boston, MA 02115, USA.
出版信息
Cell Metab. 2005 Jul;2(1):67-76. doi: 10.1016/j.cmet.2005.06.007.
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.
酿酒酵母染色质沉默因子Sir2可抑制基因组不稳定性并延长复制寿命。相比之下，我们发现缺乏哺乳动物Sir2同源物SIRT1的小鼠胚胎成纤维细胞（MEF）对复制性衰老的抵抗力显著增强。SIRT1缺陷型MEF延长的复制寿命与慢性亚致死性氧化应激条件下增殖能力的增强相关。在这种情况下，SIRT1缺陷型细胞无法正常上调p19（ARF）衰老调节因子或其下游靶点p53。然而，在急性DNA损伤或癌基因表达时，SIRT1缺陷型细胞表现出正常的p19（ARF）诱导和细胞周期停滞。总之，我们的研究结果证明了SIRT1在响应慢性细胞应激促进复制性衰老方面具有意想不到的功能，并表明p19（ARF）是该途径中的下游效应物。
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