Dissecting the mechanisms of miRNA function
Activity Code: FP7-PEOPLE-2013-CIG
Project Reference: 631482
Coordinator:Max Delbrück Zentrum für molekulare Medizin
miRNAs are crucial regulators of gene expression that target more than half of eukaryotic genes and play a role in human diseases, including cancer and neurological disorders. Therefore, it is important to understand the molecular mechanisms underlying miRNA-mediated repression. miRNAs act as guides recognizing their target mRNAs by partial complementarity and recruiting a complex of proteins that represses mRNA expression. In this complex, proteins of GW182 family are the key effectors mediating repression. We have shown that GW182 recruits deadenylation complexes via novel protein motifs (W-motifs), leading to translational repression and mRNA deadenylation. Translational repression by deadenylases occurs independently of deadenylation by a mechanism, which is still mysterious. Thus, our first goal will be (1) to analyze the mechanism of translational repression by deadenylases and its contribution to miRNA silencing. Our preliminary data show that W-motifs recruiting the deadenylation complex (CCR4-NOT) are not restricted to the GW182 family and can be found in other proteins involved in RNA metabolism. The roles of W-motifs in these proteins are completely unknown, but important to investigate if we want to better understand the mechanisms of RNA silencing. The fact that CCR4-NOT is involved not only in mRNA deadenylation and translation, but also in other steps of RNA metabolism, including transcription, RNA processing and export, suggests that proteins with W-motifs have the potential to orchestrate gene expression at different levels. Thus, our next goal will be (2) to investigate more broadly the full repressive potential of W-motifs. In a wider context, this proposal will explore the roles of miRNAs in such important and global processes as subcellular localization and translation of mRNAs. Addressing these questions will make substantial advances in our understanding of miRNA function and mechanisms of gene regulation.