NCoRSMRT

NCoRSMRT is the nuclear receptor co-repressor system formed by the paralogous corepressors NCoR1 and SMRT (silencing mediator for retinoic acid and thyroid hormone receptors). These large, multi-domain proteins function as central transcriptional corepressors in animal cells, primarily repressing target genes in the absence of ligand and in specific signaling contexts. The NCoR/SMRT family coordinates chromatin modification and transcriptional silencing through interactions with histone deacetylases and other cofactors.

Within the corepressor complexes, NCoR and SMRT recruit HDAC3, whose deacetylase activity is stimulated by the deacetylase activation domain (DAD) present in each co-repressor. The complexes also associate with GPS2 and the adaptor proteins TBL1 and TBLR1, which help stabilize the complex and regulate turnover. In the nucleus, repression is achieved in part by binding to unliganded nuclear receptors through CoRNR box motifs, enabling recruitment of HDACs and chromatin remodelers to target promoters.

Ligand binding to nuclear receptors prompts a conformational change and exchange of coregulators, leading to disassembly of the repressive complex and recruitment of coactivators. Post-translational modifications of NCoR/SMRT and their partners further modulate stability and repression strength. The NCoRSMRT system is broadly expressed and participates in diverse pathways, including metabolism, development, and circadian regulation.

Genetic or functional disruption of NCoRSMRT activity affects gene programs governing growth and metabolism and has been linked to metabolic disorders and cancer in experimental models. Because of their central role in transcriptional control, these corepressors are active areas of study for understanding hormone signaling and epigenetic regulation.