Eukaryotic translation quality control

1 PhD project offered in the IPP winter call 2023/2024

Scientific Background: Translational quality control in eukaryotic cells

Proteins are central to any living organism. To protect cells from dysfunctional and toxic, disease-causing proteins formed by aberrant translation, eukaryotic translation quality control pathways detect translation defects and remove aberrant protein products, together with associated faulty mRNA blueprints and sometimes faulty ribosomal components. Many of those pathways rely on the recognition of ribosome collisions. Much is still unknown about the molecular mechanisms underlying translation quality control, and how these interact with other cellular machineries and with organismal health and life cycle. These are research objects in my group. Besides reporter systems and polysome profiling techniques, we use sequencing-based methods, most prominently UV crosslinking and analysis of cDNA (CRAC), to study RNA-protein interactions, translation and RNA modification in the context of translation quality control. These techniques provide a unique toolbox to approach our key questions:

1: Which molecular interactions underlie translation quality control triggering and how are different targets distinguished?

2: How does translation quality control interact with cellular stress responses, translation regulation and RNA modification?

3: How does co-translational quality control work in neurons and does it change with ageing and disease?

4: What is the role of translation quality control for RNA-based and RNA-targeted therapies?

With our RNA-centred research, we want to make fundamental contributions to the understanding of translation quality control and its links to age-related neurodegenerative diseases, to ultimately inform efforts to cure, prevent or delay the onset of such diseases.

PhD Project: option 1: New players in eukaryotic translation quality control

Our group has recently discovered a number of potential new players in translation quality control by collating published information from a range of different databases and studies. We are currently investigating the potential functions of several such players in budding yeast, to define in which processes these proteins are involved and what is their molecular mechanism, using, e.g., CRAC, as well as reporter-based analyses (Müller, Tollervey, and Winz, unpublished; Iyer and Winz, unpublished).

Our current efforts so far only cover a small number of potential candidates. In this project, further candidates will be identified from published data and will be screened by reporter systems, equally in budding yeast. Positively evaluated candidates will be further studied to reveal their role in translation quality control. In addition to evaluating candidates from published screens and databases, to reveal additional candidates, new, targeted screens will be explored, followed by similar screens and evaluations.

PhD Project: option 2: Translation quality control in gene-specific translation inhibition

General inhibitors of bacterial translation play an important role as antibiotics. On the other hand, in human translation, a handful of small molecules have recently been discovered that target biosynthesis of a specific protein by targeting either the mRNA or the nascent peptide. It is now well accepted that many unspecific translation inhibitors can cause ribosome collisions and thereby trigger translation quality control pathways.

In this project, we will investigate which role translation quality control plays in specific translation inhibition in mammalian cells.

 

If you are interested in one of these projects, please select Winz as your group preference in the IPP application platform.

 

Publications relevant to this project

Bessler, Kaur, Vogt, Flemmich, Siebenaller, Winz, Tuorto, Micura, Ehrenhofer-Murray, Helm (2022) Functional integration of a semi-synthetic azido-queuosine derivative into translation and a tRNA modification circuit. Nucleic Acids Research, 50(18):10785-10800. Link

Cahová*, Winz*, Höfer*, Nübel, Jäschke (2015) NAD captureSeq indicates NAD as a bacterial cap for a subset of regulatory RNAs. Nature, 519:374- 377. (*: equal contributions). Link

Hauenschild, Tserovski, Schmid, Thüring, Winz, et al (2015) The reverse transcription signature of N-1-methyladenosine in RNA-Seq is sequence dependent. Nucleic Acids Research, 43(20):9950-9964. Link

Iyer, Müller, Tittel, Winz (2023) Molecular Highway Patrol for Ribosome Collisions. ChemBioChem Link

Khan, Mishra, Mishra, Mishra, Kumar (2019) Discovery of a Potent Small Molecule Inhibiting Huntington’s Disease (HD) Pathogenesis via Targeting CAG Repeats RNA and Poly Q Protein. Scientific Reports, 9 (1), 1–15. Link

Konieczny, Mukherjee, Stepniak-Konieczna, Taylor, Niewiadomska, Piasecka, Walczak, Baud, Dohno, Nakatani, Sobczak (2021) Cyclic Mismatch Binding Ligands Interact with Disease-Associated CGG Trinucleotide Repeats in RNA and Suppress Their Translation.Nucleic Acids Research 49 (16), 9479–9495. Link

Li, Ward, McClure, Chang, Montabana, Liras, Dullea, Cate (2019) Structural Basis for Selective Stalling of Human Ribosome Nascent Chain Complexes by a Drug-like Molecule. Nature Structural and Molecular Biology, 26 (6), 501–509. Link

Mukherjee, Błaszczyk, Rypniewski, Falschlunger, Micura, Murata, Dohno, Nakatani, Kiliszek (2019) Structural Insights into Synthetic Ligands Targeting A-A Pairs in Disease-Related CAG RNA Repeats. Nucleic Acids Research, 47 (20), 10906–10913. Link

Petersen, Hawkins, Ruangsiriluk, Stevens, Maguire, O’Connell, Rocke, Boehm, Ruggeri, Rolph, Hepworth, Loria, Carpino (2016) A Small-Molecule Anti-Secretagogue of PCSK9 Targets the 80S Ribosome to Inhibit PCSK9 Protein Translation. Cell Chemical Biology, 23 (11), 1362–1371. Link

Rzuczek, Southern, Disney (2015) Studying a Drug-like, RNA-Focused Small Molecule Library Identifies Compounds That Inhibit RNA Toxicity in Myotonic Dystrophy. ACS Chemical Biology, 10 (12), 2706–2715. Link

Winz, Cahová, Nübel, Frindert, Höfer, Jäschke (2017) Capture and sequencing of NAD-capped RNA sequences with NAD captureSeq. Nature Protocols, 12 (1), 122-149. Link

Winz, Peil, Turowski, Rappsilber, Tollervey (2019) Molecular interactions between Hel2 and RNA supporting ribosome-associated quality control. Nature Communications, 10(1), 563. Link

 

Contact Details

Dr Marie-Luise Winz
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