Project Details
Projekt
Regulation of Dicer activity by 5-lipoxygenase
Subject Area
Biochemistry
Term
since 2025
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 564834420
MicroRNAs (miRNAs) have emerged as potent regulators of gene expression involved in the post-transcriptional regulation of almost any cellular processes. 5-Lipoxygenase (5-LO) has been described to interact with Dicer, thereby modulating its enzyme activity. Originally known for its role in the biosynthesis of leukotrienes in inflammation and cancer, we could demonstrate that the interaction of 5-LO with Dicer alters the processing of the miRNA cluster miR-99b/let-7e/125a by Dicer. Thereby, 5-LO inhibits the formation of let-7e which is a well-known inducer of cell differentiation, but promotes the generation of miR-99b and miR-125a known to induce cell proliferation and the maintenance of leukemic stem cell functions. Thus, 5-LO can act as switch from the differentiation-inducing let-7e to the pro-proliferative, stemness-inducing miRs (miR-99b and 125a) to promote maintenance of stem cells and to suppress cell differentiation. We will now unravel the underlying mechanism of how 5-LO interacts with Dicer and which role the sequence and structure of the pre-miRNA plays to be recognized by the 5-LO-Dicer complex. 5-LO is mainly expressed in leukocytes. In resting monocytes, we could not detect intact Dicer. Instead the Dicer protein is cleaved into a 170 kDa and 50 kDa fragment Therefore, we want to find out whether this cleavage affects 5-LO-Dicer controlled miRNA biogenesis. The function of this proteolytic cleavage is largely unknown. Stimulation of monocytes by TLR ligands such as LPS or zymosan upregulates full-length Dicer. In this project, we will elucidate the function of Dicer cleavage in monocytes and the role of the 5-LO-Dicer interaction for miRNA biogenesis.
DFG Programme
Research Grants
