1. ¹Department of Biochemistry, McGill University, Montréal, Québec, Canada
2. ²Department of Oncology, McGill University, Montréal, Québec, Canada
3. ³McGill Cancer Center, McGill University, Montréal, Québec, Canada

Correspondence: Professor PE Branton, Department of Biochemistry, McGill University, McIntyre Medical Building, Room 702, 3655 Promenade Sir William Osler, Montréal, Québec, Canada H3G 1Y6. E-mail: philip.branton@mcgill.ca

Received 4 September 2007; Revised 29 November 2007; Accepted 3 December 2007; Published online 14 January 2008.

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 p33^ING1b and p33^ING2 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.