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

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 p33 ING2subunits 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.

ING1a expression increases during replicative senescence and induces a senescent phenotype

“…It is also possible that since ING1b and ING1a appear to act antagonistically in apoptosis assays (Fig. 4C), ING1b inhibits HDAC activity, which has recently been reported (Binda et al, 2008). Furthermore, HDAC inhibitors, which can induce euchromatin formation, can also induce a senescencelike phenotype (Ogryzko et al, 1996;Munro et al, 2004) and HDAC1 has been linked to senescence in some strains of human fibroblasts (Place et al, 2005).…”

Interference with Sin3 function induces epigenetic reprogramming and differentiation in breast cancer cells

“…Nevertheless, it will be interesting to examine the effectiveness of SID decoy in rescuing E-cadherin and ERα expression in additional triplenegative breast cancer cell lines (or sublines of MDA-MB-231 cells where the promoters of CDH1 and ESR1 are more densely methylated). It also remains to be seen whether Sirtuin inhibitors (and other epi-drugs) can synergize with the SID decoy, but it is noteworthy that SIRT1 can associate with Sin3-containing corepressor complexes through an interaction with Sin-associated protein-30 (SAP30) (29).…”

ING Proteins in Cellular Senescence

“…ING proteins do not seem to have intrinsic enzymatic activity, rather they might promote acetylation of p53 or other proteins by acting as cofactors. In support of this model, biochemical analyses have shown association of ING proteins with acetylases like p300 or PCAF [77,91] or deacetylases like SIRT1 or HDAC1 [76,80,98] all of which have the ability to regulate acetylation levels of p53. An additional level of functional interplay between p53 and ING proteins would be the role of ING proteins as transcriptional cofactors cooperating with p53 in gene regulation, possibly trough the recruitment of histone modifying complexes [99].…”

“…As mentioned above, different types of evidence support a model where ING proteins participate in transcriptional regulation through their association to complexes with chromatin-modifying activities, like HAT (histone acetyl transferase) or HDAC (histone deacetylase) [64,[76][77][78][79][80]. Specific recognisition of trimethylation of Lys4 of histone H3 (H3K4triMe), a mark of active chromatin, through their conserved PHD domain [81][82][83] would lead to the recruitment of the above mentioned complexes to the vicinity of specific gene targets, resulting in the activation or repression of these genes.…”