CNOT1 is the central scaffolding component of the CCR4-NOT complex, a master regulator of gene expression and mRNA stability 1. The complex functions as a major cellular mRNA deadenylase, with CNOT1 serving as a structural platform that recruits catalytic subunits and RNA-binding proteins to target mRNAs 2. CNOT1 mediates CCR4-NOT recruitment through multiple mechanisms: direct interaction with YTHDF2 readers of m6A-modified RNA 3, tRNA-dependent recruitment during translation 4, and P-body docking interactions 5. As a transcriptional corepressor, CNOT1 interacts with nuclear receptors to suppress gene expression, exemplified by its role in progesterone receptor signaling where it represses contractile genes in the myometrium 6. Clinically, de novo CNOT1 variants cause neurodevelopmental delay with intellectual disability, motor delay, speech delay, seizures, and behavioral problems, with evidence suggesting haploinsufficient mechanisms rather than dominant-negative effects 1. CNOT1 mutations also cause neonatal diabetes mellitus, identified among six novel NDM genes discovered between 2018-2024 7. Functional studies demonstrate that CNOT1 depletion broadly increases mRNA abundance and decreases decay rates genome-wide, with effects correlating to codon optimality 8, establishing CNOT1 as essential for normal human development and glucose homeostasis.