Figure 4. Emerging putative model of SRA RNA action on ER-α signaling.

A. Activation of ER-α gene expression by SRA RNA. Pus1p (green wheel), which is able to bind the DNA binding domain of all nuclear receptors, pseudouridylates specific SRA RNA uridine residues, leading to an optimum configuration of this RNA. The resulting SRA-ψ (cross), could now form a stabilizing complex with p68 (green crescent able to bind SRC-1 and ER-α AF-1 region) and SRC-1 (green horseshoe). Transcription of target genes with suitable ERE (red elements on DNA) will occur. It should be stressed that the physical presence of SRA RNA at the level of promoter has not yet been established experimentally. Similarly, the kinetics of events involving these molecules at the promoter site, as well as the possible effect of specific ligands (red sphere), remain to determined. B. Inhibition of SRA RNA-mediated ER-α. SLIRP (hollow red cylinder) and SHARP (hollow trapeze) act as negative regulators. It has been proposed that they might act by sequestrating SRA, by destabilizing the complex SRA/SRC-1 or by recruiting the nuclear receptor corepressor N-CoR at the promoter region of silenced genes. ER-α ligand binding domain, DNA binding domain and AF-1 domain are shown in blue horseshoe, flat elliptic cylinder and blue cylinder, respectively.