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Negative regulation of the deacetylase SIRT1 by DBC1

Abstract

SIRT1 is an NAD-dependent deacetylase critically involved in stress responses, cellular metabolism and, possibly, ageing1,2,3,4,5,6,7,8,9,10,11,12,13,14,15. The tumour suppressor p53 represents the first non-histone substrate functionally regulated by acetylation and deacetylation16,17; we and others previously found that SIRT1 promotes cell survival by deacetylating p53 (refs 4–6). These results were further supported by the fact that p53 hyperacetylation and increased radiation-induced apoptosis were observed in Sirt1-deficient mice10. Nevertheless, SIRT1-mediated deacetylase function is also implicated in p53-independent pathways under different cellular contexts, and its effects on transcriptional factors such as members of the FOXO family and PGC-1α directly modulate metabolic responses1,2,3,4,5,6,7,8,9,10,11,12,13,14,15. These studies validate the importance of the deacetylase activity of SIRT1, but how SIRT1 activity is regulated in vivo is not well understood. Here we show that DBC1 (deleted in breast cancer 1) acts as a native inhibitor of SIRT1 in human cells. DBC1-mediated repression of SIRT1 leads to increasing levels of p53 acetylation and upregulation of p53-mediated function. In contrast, depletion of endogenous DBC1 by RNA interference (RNAi) stimulates SIRT1-mediated deacetylation of p53 and inhibits p53-dependent apoptosis. Notably, these effects can be reversed in cells by concomitant knockdown of endogenous SIRT1. Our study demonstrates that DBC1 promotes p53-mediated apoptosis through specific inhibition of SIRT1.

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Figure 1: DBC1 interacts with SIRT1 in vivo and in vitro.
Figure 2: DBC1 inhibits SIRT1-mediated deacetylation of p53.
Figure 3: DBC1 acts as an inhibitor of SIRT1 in human cells.
Figure 4: siRNA-mediated knockdown of DBC1 reduces p53 acetylation and its transcriptional and apoptotic activities.

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Acknowledgements

We thank R. Baer for suggestions on this manuscript. We also thank E. White, M. Wigler and E. Verdin for reagents. This work was supported in part by Ellison Medical Foundation and grants from the National Institutes of Health/National Cancer Institute to J.Q. and W.G.

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Correspondence to Wei Gu.

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The file contains Supplementary Figures S1 – S14 with Legends and Supplementary Methods. (PDF 1447 kb)

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Zhao, W., Kruse, JP., Tang, Y. et al. Negative regulation of the deacetylase SIRT1 by DBC1. Nature 451, 587–590 (2008). https://doi.org/10.1038/nature06515

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