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

O Binda1, C Nassif, P E Branton

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

Oncogene
|January 15, 2008
PubMed

Insights

Researchers found that SIRT1, a class III HDAC, regulates RBP1-mediated transcriptional repression. ING proteins recruit SIRT1, which inhibits the activity of the mSIN3A/HDAC1 complex, revealing a novel regulatory mechanism.

Area of Science:

  • Molecular Biology
  • Cellular Biology
  • Epigenetics

Background:

  • Retinoblastoma-binding protein 1 (RBP1) and BCAA induce growth arrest and cellular senescence through transcriptional repression.
  • A genetic link between RBP1 and SIR2 (silent information regulator 2) was observed during studies of RBP1's repression activities.

Purpose of the Study:

  • To investigate the interaction between RBP1 family proteins and SIRT1 (the mammalian homologue of SIR2).
  • To elucidate the mechanism by which SIRT1 regulates RBP1-mediated transcriptional repression.
  • To propose a novel regulatory pathway involving class I and class III HDACs.

Main Methods:

  • Investigated the interaction between RBP1 and SIRT1 using in vitro and in vivo binding studies.
  • Utilized the R2 domain of RBP1, known for HDAC-dependent transcriptional repression.
  • Employed sirtuin activator resveratrol and inhibitor sirtinol in transcriptional repression assays.

Main Results:

  • The R2 domain of RBP1 is necessary and sufficient for interaction with SIRT1.
  • p33(ING1b) and p33(ING2) subunits of the mSIN3A/HDAC1 complex mediate SIRT1 recruitment to the R2 domain.
  • SIRT1 activity was found to negatively regulate R2-mediated transcriptional repression.

Conclusions:

  • Proposed a novel mechanism where a class III HDAC (SIRT1) regulates a class I HDAC complex (mSIN3A/HDAC1).
  • SIRT1, recruited by ING proteins, inhibits the transcriptional repression activity associated with the RBP1 R2 domain.
  • This interaction provides new insights into the crosstalk between different HDAC classes in regulating gene expression.

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