A conserved alpha-helical motif mediates the interaction of Sp1-like transcriptional repressors with the corepressor mSin3A

Sp1-like proteins are defined by three highly homologous C2H2 zinc finger m otifs that bind GC-rich sequences found in the promoters of a large number of genes essential for mammalian cell homeostasis. Here we report that TIEG 2, a transforming growth factor beta -inducible Sp1-like protein with antip roliferative functions, represses transcription through recruitment of the mSin3A-histone deacetylase complex. The interaction of TIEG2 with mSin3A is mediated by an alpha-helical repression motif (alpha -HRM) located within the repression domain (R1) of TIEG2. This alpha -HRM specifically associate s with the second paired amphipathic helix (PAH2) domain of mSin3A. Mutatio ns in the TIEG2 alpha -HRM domain that disrupt its helical structure abolis h its ability to both bind mSin3A and repress transcription. Interestingly, the alpha -HRM is conserved in both the TIEG (TIEG1 and TIEG2) and BTEB (B TEB1, BTEB3, and BTEB4) subfamilies of Sp1-like proteins. The alpha -HRM fr om these proteins also mediates direct interaction with mSin3A and represse s transcription. Surprisingly, we found that the alpha -HRM of the Sp1-like proteins characterized here exhibits structural and functional resemblance to the Sin3A-interacting domain previously described for the basic helix-l oop-helix protein Mad1. Thus, our study defines a mechanism of transcriptio nal repression via the interactions of the alpha -HRM with the Sin3-histone deacetylase complex that is utilized by at least five Sp1-like transcripti onal factors. More importantly, we demonstrate that a helical repression mo tif which mediates Sin3 interaction is not an exclusive structural and func tional characteristic of the Mad1 subfamily but rather has a wider function al impact on transcriptional repression than previously demonstrated.