Alternative splicing determines the interaction of SMRT isoforms with nuclear receptor-DNA complexes

Flavie Faist , Stephen Short , Gg Kneale , Colin R Sharpe (1)

1 School of Biological Sciences

Signalling by small molecules such as retinoic acid is mediated by heterodimers consisting of a class II nuclear receptor and an RXR subunit. The receptors bind to DNA response elements and act as ligand-dependent transcription factors but, in the absence of signal, the receptors bind the corepressors SMRT and NCoR and repress gene expression. Alternative splicing of the SMRT transcript in mammals generates six isoforms containing 1, 2 or 3 CoRNR box motifs that are responsible for the interactions with nuclear receptors. We show that human cell lines express all six SMRT isoforms and then determine the binding affinity of mouse SMRT isoforms for RAR/RXR and three additional class II nuclear receptor-DNA complexes. This approach demonstrates the importance of the full complement of CoRNR boxes within each SMRT protein, rather than the identity of individual CoRNR boxes, in directing the interaction of SMRT with nuclear receptors. Each class of SMRT isoform displays a distinct feature as the 1-box isoform discriminates between DNA response elements, the 2-box isoforms promote high affinity binding to thyroid hormone receptor complexes and the 3-box isoforms show differential binding to nuclear receptors. Consequently, the differential deployment of SMRT isoforms seen in vivo could significantly expand the regulatory capacity of nuclear receptor signalling.

Mots clés: Life Sciences

Flavie Faist, Stephen Short, Gg Kneale, Colin R Sharpe. Alternative splicing determines the interaction of SMRT isoforms with nuclear receptor-DNA complexes. Bioscience Reports, 2009, 29 (3), pp.143-149. ⟨10.1042/BSR20080093⟩. ⟨hal-00479306⟩