Mechanistic and functional characterization of Makorin 1 mRNPs

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The Makorin (Mkrn) proteins are an evolutionarily highly conserved family of RNA-binding proteins (RBPs) with an E3 ubiquitin ligase function. This project aims to unravel the function of Mkrn1 mRNPs (mRNA ribonucleoprotein complexes) in the posttranscriptional regulation of gene expression. We focus on two complementary systems, Drosophila as a well-established model organism for embryonic development, as well as human cell lines for complex regulatory scenarios with potential relevance in human physiology.In the first funding period, we have combined developmental studies with state-of-the-art ribonomics and proteomics approaches to address the roles of Mkrn1 in Drosophila oogenesis and human translation. Intriguingly, we have found that in both organisms, Mkrn1 interacts with the poly(A)-binding protein and binds to mRNAs specifically upstream of poly(A) sequences. In a line of experiments, we could show that human MKRN1 serves in ribosome-associated quality control, while Mkrn1 binding in Drosophila specifically regulates the translation of oskar mRNA to control embryonic patterning. In the second funding period, we will continue to integrate cell biology, biochemistry and high-throughput approach with computational biology to study the mechanistic principles of Mkrn1 function. We will characterize the components of the Mkrn1 mRNPs, dissect their functional interactions and follow their link to mRNA modifications. Our parallel approaches in Drosophila and human cells will enable us to illuminate Mkrn1 function from different molecular and evolutionary perspectives.