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SIRT1 negatively regulates HDAC1-dependent transcriptional repression by the RBP1 family of proteins

Oncogene volume 27, pages 3384–3392 (2008)Cite this article

Abstract

Both RBP1 and the highly related protein BCAA play a role in the induction of growth arrest and cellular senescence via mechanisms involving transcriptional repression. While investigating the transcriptional repression activities of RBP1, we observed a genetic link between RBP1 and SIR2. Further work uncovered an interaction between RBP1 family proteins and the mammalian homologue of SIR2, SIRT1. Interestingly, the HDAC-dependent transcriptional repression domain of RBP1 proteins, termed R2, is necessary and sufficient for the interaction with SIRT1. In vitro and in vivo binding studies indicated that the p33ING1b and p33ING2 subunits of the mSIN3A/HDAC1 complex are responsible for the recruitment of SIRT1 to the R2 domain. To investigate the biological relevance of this interaction, we used the sirtuin activator resveratrol and the sirtuin inhibitor sirtinol in transcriptional repression assays and demonstrated that SIRT1 activity negatively regulates R2-mediated transcriptional repression activity. We therefore propose a novel mechanism of class I HDAC regulation by a class III HDAC. Explicitly, SIRT1 is recruited by ING proteins and inhibits R2-associated mSIN3A/HDAC1 transcriptional repression activity.

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Acknowledgements

We thank Laurent Huck and Peter Moffett for critically reviewing this manuscript, and Jean-Sébastien Roy for valuable discussions. This work was supported through grants from the Canadian Cancer Society, the National Cancer Institute of Canada and the Canadian Institutes for Health Research.

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Authors and Affiliations

  1. Department of Biochemistry, McGill University, Montréal, Québec, Canada

    O Binda, C Nassif & P E Branton

  2. Department of Oncology, McGill University, Montréal, Québec, Canada

    P E Branton

  3. McGill Cancer Center, McGill University, Montréal, Québec, Canada

    P E Branton

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  1. O Binda
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Correspondence to P E Branton.

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

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Binda, O., Nassif, C. & Branton, P. SIRT1 negatively regulates HDAC1-dependent transcriptional repression by the RBP1 family of proteins. Oncogene 27, 3384–3392 (2008). https://doi.org/10.1038/sj.onc.1211014

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