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DBC1 is a negative regulator of SIRT1

Abstract

The NAD-dependent protein deacetylase Sir2 (silent information regulator 2) regulates lifespan in several organisms1,2,3. SIRT1, the mammalian orthologue of yeast Sir2, participates in various cellular functions4,5,6,7 and possibly tumorigenesis8. Whereas the cellular functions of SIRT1 have been extensively investigated, less is known about the regulation of SIRT1 activity. Here we show that Deleted in Breast Cancer-1 (DBC1), initially cloned from a region (8p21) homozygously deleted in breast cancers9, forms a stable complex with SIRT1. DBC1 directly interacts with SIRT1 and inhibits SIRT1 activity in vitro and in vivo. Downregulation of DBC1 expression potentiates SIRT1-dependent inhibition of apoptosis induced by genotoxic stress. Our results shed new light on the regulation of SIRT1 and have important implications in understanding the molecular mechanism of ageing and cancer.

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Figure 1: DBC1 interacts with SIRT1 in vivo.
Figure 2: The leucine zipper motif of DBC1 and the catalytic domain of SIRT1 are required for the DBC1–SIRT1 interaction.
Figure 3: DBC1 inhibits SIRT1 deacetylase activity in vitro and in vivo.
Figure 4: DBC1 regulates SIRT1 function after stress stimuli.

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Acknowledgements

We thank E. White for providing DBC1 expression constructs. We thank T. P. Yao, R. Janknecht, M. Huen and M. H. Sy for providing constructs encoding SIRT1, p300, p53 and Myc, respectively. This work was supported in part by grants from the National Institutes of Health (to J.C). Z.L was supported by a Susan G. Komen Breast Cancer Foundation Research Grant. J.C. is a recipient of an Era of Hope Scholars award from Department of Defense and a member of Mayo Clinic Breast SPORE program.

Author Contributions J.K. and Z.L. performed the experimental work and data analysis. J.K., J.C. and Z.L. wrote the paper. All authors discussed the results and commented on the manuscript.

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Correspondence to Junjie Chen or Zhenkun Lou.

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Kim, JE., Chen, J. & Lou, Z. DBC1 is a negative regulator of SIRT1. Nature 451, 583–586 (2008). https://doi.org/10.1038/nature06500

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