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Role of 2-5A-dependent RNase-L in senescence and longevity

Abstract

Senescence is a permanent growth arrest that restricts the lifespan of primary cells in culture, and represents an in vitro model for aging. Senescence functions as a tumor suppressor mechanism that can be induced independent of replicative crisis by diverse stress stimuli. RNase-L mediates antiproliferative activities and functions as a tumor suppressor in prostate cancer, therefore, we examined a role for RNase-L in cellular senescence and aging. Ectopic expression of RNase-L induced a senescent morphology, a decrease in DNA synthesis, an increase in senescence-associated β-galactosidase activity, and accelerated replicative senescence. In contrast, senescence was retarded in RNase-L-null fibroblasts compared with wild-type fibroblasts. Activation of endogenous RNase-L by 2-5A transfection induced distinct senescent and apoptotic responses in parental and Simian virus 40-transformed WI38 fibroblasts, respectively, demonstrating cell type specific differences in the antiproliferative response to RNase-L activation. Replicative senescence is a model for in vivo aging; therefore, genetic disruption of senescence effectors may impact lifespan. RNase-L−/− mice survived 31.7% (P<0.0001) longer than strain-matched RNase-L+/+ mice providing evidence for a physiological role for RNase-L in aging. These findings identify a novel role for RNase-L in senescence that may contribute to its tumor suppressive function and to the enhanced longevity of RNase-L−/− mice.

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Acknowledgements

We thank Dennis Stacey, Cleveland Clinic Foundation, for performing the microinjection experiments. We thank Dr Paul Torrence, Northern Arizona State University, for providing 2-5A. This work was supported by Grant AG20355 from the NIA, NIH, to BAH, a Glenn/American Federation for Aging Research Scholarship to CSJ, and a Grant from NIH, NCI CA044059 to RHS.

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Correspondence to B A Hassel.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Andersen, J., Li, X., Judge, C. et al. Role of 2-5A-dependent RNase-L in senescence and longevity. Oncogene 26, 3081–3088 (2007). https://doi.org/10.1038/sj.onc.1210111

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