About Marina Chekulaeva
Throughout my research career, my main focus was on the mechanisms of post-transcriptional gene regulation. I have a background in the fields of RNA biology, miRNAs, translational control, mRNA localization, and neurobiology. I received my first intensive training in molecular biology in the laboratory of Dr. Alexander Spirin (Institute for Protein Research, Puschchino, Russia), where I worked on establishing the continuous-exchange in vitro translation system (Chekulayeva et al., 2001). For my Ph.D. project, I joined the laboratory of Dr. Anne Ephrussi (EMBL, Heidelberg) to investigate the mechanism that regulates the translation of oskar mRNA, the determinant of Drosophila posterior structures. My Ph.D. at the EMBL was supported by a fellowship from the Louis-Jeantet Foundation for Medicine (Geneva, Switzerland), which aims at promoting the careers of young researchers from Eastern Europe. My Ph.D. work has uncovered a novel repression mechanism that involves mRNA oligomerization into unusually large RNP complexes that cannot be accessed by ribosomes. This unprecedented mechanism of translational control is particularly suited to couple translational control with mRNA transport, a common and ill-understood theme, particularly in developmental and neurobiology. This work resulted in a publication in Cell (Chekulaeva et al. 2006).
Already during my Ph.D., I became interested in the emerging field of small RNAs (Chekulaeva and Ephrussi 2004). Therefore for my postdoctoral studies, I joined the labs of Dr. Witek Filipowicz (Friedrich Miescher Institute, Switzerland) and Dr. Roy Parker (University of Arizona, USA) to dissect the mechanisms of miRNA function. I was awarded six postdoctoral fellowships, three of which I gratefully declined. The function of GW182, the effector protein of the miRNA repression complex, was unclear, and I aimed to investigate it. I have shown that both human and Drosophila GW182 proteins function through novel tryptophane-containing motifs (W-motifs) acting in an additive manner to recruit the CCR4-NOT deadenylation complex and repress mRNA. When inserted into a heterologous yeast polypeptide, these key silencing motifs were able to repress tethered mRNA and interact with the CCR4–NOT complex, demonstrating that W-motifs are not only necessary but also sufficient for repression. Recruited components of the CCR4-NOT complex repressed both poly(A)+ and poly(A)- mRNAs, showing that deadenylation complexes repress translation of their target mRNAs via a novel mechanism independent of their deadenylation activity. These findings reconciled literature data that could not be explained by previous models and provided a new foundation from which to explore miRNA function. My postdoctoral work resulted in four first-author manuscripts (Chekulaeva and Filipowicz 2009; Chekulaeva et al. 2009; Chekulaeva et al. 2010; Chekulaeva et al. 2011). My finding of the silencing W-motifs mediating miRNA function has been published in Nature Structural and Molecular Biology (Chekulaeva et al. 2011).
Through competitive procedures, I was selected for an independent group leader position at the Berlin Institute for Medical Systems Biology (BIMSB), a part of the Max-Delbrück-Center (MDC) that integrates high-throughput systems biology approaches with molecular biology and genetics to address important questions in fundamental biological research. My lab focuses on RNA localization in neurons and neurodegeneration. For example, my lab has uncovered a key role of mRNA localization in the establishment of cell polarity in neurons, accounting for more than half of the neurite-localized proteome (Zappulo et al. Nature Com 2017) and demonstrated that alternative 3’UTRs direct localization of functionally diverse protein isoforms in neuronal compartments (Ciolli Mattioli et al. NAR 2019). We also develop new technologies for the analysis of RNA localization. For instance, our neuronal zipcode identification protocol (N-zip, Mendonsa et al. Nature Neuroscience) can identify zipcodes across hundreds of mRNAs. N-zip provided the first demonstration of a miRNA affecting mRNA localization and suggested a strategy for detecting many more zipcodes. We apply our know-how to understand the mechanisms behind motor neuron degeneration. For example, my lab has revealed the mechanisms of function of mutations in glycyl-tRNA synthetase (GARS), causative of Charcot–Marie–Tooth (CMT) disease (Mendonsa et al. NAR 2021). We showed that mutant GARS depletes the pool of glycyl-tRNA available for translation and causes ribosomes to pause at glycine codons, which in turn activates the integrated stress response (ISR). These findings suggested a supply of tRNA and inhibition of ISR as therapeutic strategies in CMT.
Besides research, I enjoy teaching undergraduate students. I employ active learning and include a strong discussion component and collaborative problem-solving in my lectures, seminars, and practicals. To formalize my extensive teaching experience (> 300 hours), I have completed my Habilitation (German teaching degree) at the Biochemistry Department of the Free University Berlin. In my teaching portfolio, there is a methods module on ribosome profiling (Biochemistry Master program, Free University), lectures on post-transcriptional gene regulation and RNA-based therapies (Molecular Medicine Master program, Charité), lectures on RNA transport and translational control (Free University, Humboldt University), lectures and seminars on biochemistry and molecular biology (Bioinformatics Bachelor program, Free University, in German), and others. I also have experience with the unique Oxford tutorial system, which represents a meeting with small groups of students to provide individual training in critical thinking, scientific discussion, and essay writing.