Zhang, Z., Feng, J., Pan, C., Lv, X., Wu, W., Zhou, Z., Liu, F., Zhang, L., and Zhao, Y. (2013) Atrophin-Rpd3 complex represses Hedgehog signaling by acting as a corepressor of CiR. The Journal of cell biology. 203(4):575-583.
The evolutionarily conserved Hedgehog (Hh) signaling pathway is transduced by the Cubitus interruptus (Ci)/Gli family of transcription
factors that exist in two distinct repressor (CiR/GliR) and activator (CiA/GliA) forms. Aberrant activation of Hh signaling is associated with various human cancers, but the mechanism through which CiR/GliR properly represses target gene expression is poorly understood. Here, we used Drosophila melanogaster and zebrafish models to define a repressor function of Atrophin (Atro) in Hh signaling. Atro directly bound to Ci through
its C terminus. The N terminus of Atro interacted with a histone deacetylase, Rpd3, to recruit it to a Ci-binding site at
the decapentaplegic (dpp) locus and reduce dpp transcription through histone acetylation regulation. The repressor function of Atro in Hh signaling was dependent on Ci.
Furthermore, Rerea, a homologue of Atro in zebrafish, repressed the expression of Hh-responsive genes. We propose that the
Atro–Rpd3 complex plays a conserved role to function as a CiR corepressor.