The most well characterized nuclear receptor corepressors are SMRT and its close paralog NCoR1. NCoR1 functions to transcriptionally silence various unliganded, DNA bound non-steroidal nuclear receptors by serving as a large molecular scaffold that bridges the receptors with multiple chromatin remodeling factors that repress nuclear receptor-mediated gene transcription, in part, through deacetylation of core histones surrounding target promoters. Indeed, the N-terminal portion of NCoR1 possesses multiple distinct transcriptional repression domains reponsible for the recruitment of additional components of the corepressor complex such as HDACs, mSin3, GPS2, and TBL1/TBLR1. In between the RDs lies a pair of potent repressor motifs known as SANT motifs, which recruit HDAC3 and histones to the repressor complex in order to enhance HDAC3 activity. The C-terminal portion of NCoR1 contains multiple nuclear receptor interaction domains, each of which contains a conserved CoRNR box motif that allow for binding to various unliganded nuclear hormone receptors such as thyroid hormone and retinoic acid receptors.Recent genetic studies in mice have not only corroborated the wealth of biochemical studies involving NCoR1 but have also provided significant insight regarding the function of NCoR1 in mammalian development and physiology. Although it has been observed that loss of Ncor1 does not affect early embyonic development, likely due to compensation by Smrt, embryonic lethality ultimately results during mid-gestation, largely due to defects in erythropoesis and thymopoesis. Another study demonstrated that the NDs of NCoR1 are critical for its ability to function in a physiological setting as a transcriptional repressor of hepatic THR and Liver X Receptor.
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