👤 Ania Wilczynska

The CCR4-NOT complex plays an important role in the translational repression and deadenylation of mRNAs. However, little is known about the specific roles of interacting factors. We demonstrate that the DEAD-box helicases eIF4A2 and DDX6 interact directly with the MA3 and MIF domains of CNOT1 and compete for binding. Furthermore, we now show that incorporation of eIF4A2 into the CCR4-NOT complex inhibits CNOT7 deadenylation activity in contrast to DDX6 which enhances CNOT7 activity. Polyadenylation tests (PAT) on endogenous mRNAs determined that eIF4A2 bound mRNAs have longer poly(A) tails than DDX6 bound mRNAs. Immunoprecipitation experiments show that eIF4A2 does not inhibit CNOT7 association with the CCR4-NOT complex but instead inhibits CNOT7 activity. We identified a CCR4-NOT interacting factor, TAB182, that modulates helicase recruitment into the CCR4-NOT complex, potentially affecting the outcome for the targeted mRNA. Together, these data show that the fate of an mRNA is dependent on the specific recruitment of either eIF4A2 or DDX6 to the CCR4-NOT complex which results in different pathways for translational repression and mRNA deadenylation. Show less

The impact of diet and environmental factors on genes concerned with epigenetic inheritance and the mechanism of evolution has grown significantly beyond the Modern Synthesis period. Epigenetic inheritance is the passing of phenotypic change to subsequent generations in ways that are outside the genetic code of DNA. Recently, polymorphisms of the human Delta-5 (fatty acid desaturase, FADS1) and Delta-6 (FADS2) desaturase genes have been described as being associated with the level of several long-chain n-3 and n-6 polyunsaturated fatty acids (PUFAs) in serum phospholipids. Increased consumption of refined starches and sugar increases the generation of superoxide anion in the tissues and free fatty acids (FFA) in the blood. There is an increased amount and activity of nuclear factor-κB (NF-κB), a transcriptional factor regulating the activity of at least 125 genes, most of which are pro-inflammatory. The consumption of glucose may be associated with an increase in 2 other pro-inflammatory transcription factors: activating protein-1 (AP-1), and early growth response protein-1 (Egr-1). AP-1 regulates the transcription of matrix metallo-proteinases and Egr-1 modulates the transcription of tissue factor and plasminogen activator inhibitor-1. It is possible that a complex set of factors, including nutritional factors, come into play during epigenetic inheritance. Show less