O-GlcNAcylation is a dynamic nucleocytoplasmic protein modification that serves as a nutrient sensor and regulator of nearly every cellular process. O-GlcNAcylation is required for life in mammals and plants, and its dysregulation has been described in numerous diseases including cancer, diabetes, cardiovascular disease, and neurodegeneration. Yet, in mammals there is only one gene encoding the O-GlcNAc Transferase (OGT). OGT activity and substrate selectivity are highly sensitive to its donor-sugar concentration: the UDP-GlcNAc, which is a perfect nutrient sensor since its biosynthesis is directly coupled to flux through glucose, amino acid, fatty acid and energy metabolism. O-GlcNAcylation is critically important to nutrient regulation of transcription, signaling and progression through cell cycle. Thus, O-GlcNAcylation plays critical roles in nearly all aspects of cellular physiology. 

Gene transcription is an evolutionary conserved cell mechanism requested to sustain cell homeostasis. It is performed by three RNA polymerases (RNAP) each of them devoted to a subset of gene. Correct recruitment of specific RNAP involves the dedicated assembly of dozens of factors on promoters to form the pre-initiation complex (PIC) competent for gene transcription initiation. Except for perhaps RNA polymerases, TATA-binding protein (TBP) is arguably the most important protein in transcription since its initial binding to DNA is the first step in the assembly at promoters of the complex machinery that ultimately transcribes genes. Although originally thought to be a platform requested to scaffold the PIC, our very recent data shed a light on the regulation of transcription through the dynamic modification of TBP by O-GlcNAcylation.